Hydrolysable linkers and cross-linkers for absorbable polymers

ABSTRACT

The present invention relates to the discovery of new class of linear and multiarmed hydrolysable linkers and cross linkers for use in the synthesis of biodegradable polymers such as, polyesters, polyurethanes, polyamides, polyureas and degradable epoxy amine resin. The linear and multiarmed hydrolysable linkers of the present invention include symmetrical and/or unsymmetrical ether carboxylic acids, amines, amide diols, amine polyols and isocyanates.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Application No. 60/972,855,filed Sep. 17, 2007, the disclosure of which is hereby incorporatedherein by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates a new class of linear and multiarmedhydrolysable linkers and cross linkers and their synthetic intermediatesfor applications that include the synthesis of biodegradable polymerssuch as, polyesters, polyurethanes, polyamides, polyureas, anddegradable epoxy amine resin. The linear and multiarmed hydrolysablelinkers of the present invention include symmetrical and/orunsymmetrical ether carboxylic acids, amines, amide diols, aminepolyols, and isocyanates.

BACKGROUND OF THE INVENTION

Much work has been accomplished in the last 20 years in the area ofhydrophobic biodegradable polymers, wherein the biodegradable moietiesinclude esters, lactones, orthoesters, carbonates, phosphazines, andanhydrides. Generally the polymers made of these biodegradable linkagesare not water-soluble and therefore in themselves are not amenable foruse in systems where water is required, such as in hydrogels.

Since the mechanism of biodegradation in these polymers is generallythrough the hydrolytically-active components of water (hydronium andhydroxide ions), the rate of hydrolytic scission of the bonds holding apolymer network together is generally pH sensitive, with these moietiesbeing susceptible to both specific-acid catalyzed hydrolysis and basehydrolysis. Other factors affecting the degradation of materials made ofthese polymers are the degree of polymer crystallinity, the polymervolume fraction, the polymer molecular weight, the cross-link density,and the steric and electronic effects at the site of degradation.

Biodegradable network structures are prepared by placing covalent ornon-covalent bonds within the network structure that may be broken underbiologically relevant conditions. This involves the use of two separatestructural motifs. The degradable structure is either placed into (i)the polymer backbone or (ii) into the cross-linker structure. In 1983, asystem of degradable hydrogels was disclosed that reportedly included awater-soluble linear copolymer containing PEG, glycolylglycolic acid,and fumaric acid linkages (Heller, J.; Helwing, R. F.; Baker, R. W.; andTuttle, M. E. “Controlled release of water-soluble macromolecules frombioerodible hydrogels.” Biomaterials, 4; (1983) 262-266). The fumaricacid reportedly allowed the linear polymer to be cross-linked throughfree radical polymerization in a second network forming polymerizationstep, thus creating a polymer network that could degrade throughhydrolysis of the glycolic ester linkages. This is an example ofcreating degradable linkages in the polymer backbone.

Biodegradable Cross-linkers: The first truly degradable cross-linkingagents were reportedly made from aryl diazo compounds for delivery ofdrugs in the digestive tract. According to Brondsted (Brondsted, H.; andKopccek, J. “Hydrogels for site-specific oral drug deliver: synthesisand characterization.” Biomaterials, 12; (1991) 584-592), the diazomoiety may be cleaved by a bacterial azoreductase that is present in thecolon. These agents are reportedly useful in the creation of colonspecific delivery systems. A bis-vinylic compound based on hydroxylaminehas been disclosed as a biodegradable cross-linking agent by Ulbrich andDuncan (Ulbrich, K.; Subr, V.; Seymour, L. W.; and Duncan, R. “Novelbiodegradable hydrogels prepared using the divinylic crosslinking agentN,O-dimethacryloylhydroxylamine. 1. Synthesis and characterisation ofrates of gel degradation, and rate of release of model drugs, in vitroand in vivo.” Journal of Controlled Release, 24; (1993) 181-190).Hydrogels made from this degradable cross-linker were said to undergohydroxide-induced hydrolysis of the nitrogen-oxygen bond.

Hubbell et al. (U.S. Pat. Nos. 5,801,033; 5,834,274; and 5,843,743) havedisclosed hydrogels composed of macro monomers derived in a multi stepsynthetic process. According to Hubbell, the macromonomers are composedof a central PEG diol which was transesterified using tin octanoatecatalyzed ring opening polymerization of lactide to give abis-oligolactate PEG. Following this step, the resultantbis-oligolactate PEG was then reportedly reacted with acryloyl chlorideto give a macromolecular cross-linker. Hubbell disclosed that themacromolecular cross-linker could be converted into a homo-polymerinterpenetrating network of PEG and oligolacetylacrylate through freeradical polymerization (Pathak et al, U.S. Pat. No. 6,887,974). Hubbell(U.S. Pat. Nos. 5,801,033; 5,834,274; and 5,843,743) disclosed thesecompounds as photopolymerizable homo-polymers reportedly useful inpreventing surgical adhesion.

Van Dijk-Wolthius et al. (van Dijk-Wolthuis, W. N. W.; Hoogeboom, J.;van Steenbergen, M.; Tsang, S.; and Hennick, W. “Degradation and ReleaseBehavior of Dextran-Based Hydrogels.” Macromolecules, 30; (1997)4639-4645; van Dijk-Wolthuis, W. N. E.; Tsang, S.; Kettenes-van denBosch, J.; and Hennick, W. “A new class of polymerizable dextrans withhydrolyzable groups: hydroxyethyl methacrylated dextran with and withoutoligolactate spacer.” Polymer, 38(25); (1997) 6235-6242) has recentlyreported a second solution to this problem, using a biodegradablecross-linking macromonomer composed of alpha-hydroxy esters This workreportedly combines natural polymers with synthetic polymers in aninterpenetrating network. This group disclosed functionalized dextranwith oligo-alpha-hydroxy acid domains, which were end capped with vinylregions that were polymerized into biodegradable networks via freeradical polymerization.

The most recent report of a biodegradable cross-linking agent involvedan agent designed to undergo enzymatic degradation. This cross-linker isindicated to include a centro-symmetric peptide terminated by acrylamidemoieties with a central diamine linking the two ends (Kurisawa et al,Macromol. Chem. Phys. 199, 705-709 (1998).

Pathak (U.S. Pat. No. 6,887,974) described polymeric cross-linkingagents reportedly having an inert water-soluble polymeric component, abiodegradable component, and functional components that are reactivewith chemical groups on a protein such as amine or thiol. According toPathak, the inert polymeric component may be flanked at each end with abiodegradable component, which is flanked at each end with a proteinreactive functional component. Pathak also disclosed a polymericcrosslinking agent having a biodegradable component, polyalkylene oxide,and at least three reactive functional groups, each of them reportedlycapable of forming a covalent bond in water with at least one functionalgroup such as an amine, thiol, or carboxylic acid.

Ashton et al. (US Patent Application Ser. No. 20030158598) disclosedmedical devices having a coating disposed on at least one surface,wherein the coating reportedly includes a polymer matrix and a lowsolubility anti-inflammatory corticosteroid formulation or lowsolubility codrug or prodrug of an anti-inflammatory corticosteroidformulation.

Uhrich et al (US Patent Application Ser. No. 20040096476) describedtherapeutic devices including a polymeric anti-inflammatory agent thatreportedly biodegrades to release anti-inflammatory agents. Thetherapeutic devices are disclosed as being useful for repair andregeneration of a variety of injured tissues.

Carpenter, et al, (US Patent Application Ser. No. 20050238689) discloseda bioactive implantable stent including a stent structure with a surfacecoating of a biodegradable, bioactive polymer, wherein the polymers saidto include at least one bioligand covalently bound to the polymer andwherein the bioligand are said to specifically bind to integrinreceptors on progenitors of endothelial cells (PECs) in circulatingblood.

Giroux (US Patent Application Ser. No. 20060013851) describedpolyanhydrides which link low molecular weight drugs containing acarboxylic acid group and an amine, thiol, alcohol, or phenol groupwithin their structure into polymeric drug delivery systems. Alsoreported are methods of producing polymeric drug delivery systems viathese polyanhydride linkers as well as methods of administering lowmolecular weight drug to a host via the polymeric drug delivery systems.Medical implants based on the polymeric drug delivery system of theinvention are also disclosed.

The use of isocyanate linkers to make hydrolysable active agentbiopolymer conjugates was described in WO2004008101.

Biodegradable linkers for molecular therapies were described inWO2006052790.

Ptchelintsev et al. described the use of oxa acids and related compoundsfor treatment of skin conditions in U.S. Pat. Nos. 5,932,229 and5,834,513 respectively.

Kiser et al. (U.S. Pat. No. 5,521,431) disclosed biodegradablecross-linkers having a polyacid core with at least two acidic groupscovalently connected to reactive groups reportedly usable to cross-linkpolymer filaments. A biodegradable region is disclosed by Kiser betweenat least one reactive group and an acidic group of the polyacidpreferably consisting of a hydroxyalkyl acid ester sequence having 1 to6 hydroxyalkyl acid ester groups.

According to Kiser, the polyacid may be attached to a water-solubleregion that is attached to the biodegradable region having attachedreactive groups. Lactate or glycolate is reportedly preferred as thehydroxyalkyl acid ester group. Polyacids include diacids; triacids,tetraacids, pentaacids and the reactive group may contain acarbon-carbon double bond. A network of cross-linked polymer filamentshaving a defined biodegradation rate is said to be formed using thecross-linkers. Kiser discloses that the network may contain biologicallyactive molecules, and may be in the form of a microparticle ornanoparticle, or hydrogel. The polymer filaments are reportedly derivedfrom polymer filaments of polynucleic acids, polypeptides, proteins orcarbohydrates. Reportedly, the cross-linkers may be copolymerized withcharged monomers such as acrylic monomers containing charged groups.Applications of the cross-linkers and network are said to includecontrolled release of drugs and cosmetics, tissue engineering, woundhealing, hazardous waste remediation, metal chelation, swellable devicesfor absorbing liquids and prevention of surgical adhesions.

In U.S. Pat. No. 4,829,099, Fuller disclosed metabolically acceptablepolyisocyanate or polyisothiocyanate monomers as tissue adhesives. Moreparticularly, this invention discloses surgical adhesive polymersderived from these polyisocyanate monomers, wherein the surgicalpolymers do not metabolize to toxic products. Amine precursors of thesepolyisocyanates were not isolated or identified and were not describedfor any applications.

The majority of biodegradable polymers are not soluble in water. As aconsequence, a hydrophilic drug must be formulated in these polymers by,for example, a dispersion method using a two-phase system of water(containing drug) and organic solvent (containing the polymer). Thesolvent is removed by evaporation resulting in a solid polymercontaining aqueous droplets. This type of system suffers from the needto use organic solvents. The use of these solvents is undesirable forprotein delivery and may lead to denaturation of the protein, amongother things.

Several problems associated with prior art biodegradable polymers havelimited their commercial use. Biodegradable polymers typically have apolydispersed molecular architecture, which at least in part, is afunction of their standard mode of preparation, i.e., stepwisecondensation. As an undesirable consequence of this stepwisecondensation, the resultant material will contain cross-links with avariety of degradation rates, in contrast to a more preferred tunabledegradation profile, because the rate of degradation is related to thepolydispersed molecular architecture. Synthetic biodegradable polymersare generally water insoluble as are a significant number of theirprecursors. The water insolubility of these materials adversely affectstheir biodegradability. Thus, there is a need for enhancing watersolubility to improve biodegradability of certain polymers.

Thus, there is still an unfulfilled need for new materials (e.g.,linkers and polymers derived therefrom) that are easily synthesized,composed of biocompatible components, and/or have improved watercompatibility, that avoid the use of during their use in drugformulation, and/or have a well defined and/or controllable molecularstructure leading to defined biodegradation rates. The present inventionis directed to these, as well as other important ends.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides biologically-acceptableand biodegradable linear and multiarmed linkers and cross-linkers withtunable degradation profiles.

In other aspects, the present invention provides linear and multiarmedhydrolysable monomeric and/or oligomeric linkers, or pharmaceuticallyacceptable salts thereof of formulas I, II, III, or IV:R[—C(═O)—(Y)_(a)—O—R¹]_(w)  IR[—(X)_(a)—OC(═O)—R²]_(w)  IIR[—(Y)_(a)—O—R³]_(w)  IIIR⁴—O—(Y¹)_(c)—O—(Y)_(d)—O—R⁴  IV

wherein:

-   -   each —O—R¹, —O—R³, —O—R⁴, and R⁴—O— is independently:

-   -   each —OC(═O)—R² is independently:

-   -   each Z is independently: NH₂, NH(Y¹)_(b)H, N((X¹)_(b)H)₂, NCO,        CH₂CO₂H, or CH═CHCO₂H;    -   each X is independently:        -   —OC(═O)CH₂— (inverse glycolic acid moiety), —OC(═O)CH(CH₃)—            (inverse lactic acid moiety), —OC(═O)CH₂OCH₂CH₂— (inverse            dioxanone acid moiety), —OC(═O)CH₂CH₂CH₂CH₂CH₂— (inverse            caprolactone acid moiety), —OC(═O)(CH₂)_(y)—, or            —OC(═O)CH₂(OCH₂CH₂)_(z)—.    -   each X¹ is independently:        -   —CH₂C(═O)O— (glycolic acid moiety), —CH(CH₃)C(═O)O— (lactic            acid moiety), —CH₂CH₂OCH₂C(═O)O— (dioxanone acid moiety),            —CH₂CH₂CH₂CH₂CH₂C(═O)O— (caprolactone acid moiety),            —(CH₂)_(y)C(═O)O—, or —(CH₂CH₂O)_(z)CH₂C(═O)O—;    -   each Y is independently:        -   —OCH₂C(═O)— (inverse glycolic ester moiety), —OCH(CH₃)C(═O)—            (inverse lactic ester moiety), —OCH₂CH₂OCH₂C(═O)— (inverse            dioxanone ester moiety), —OCH₂CH₂CH₂CH₂CH₂C(═O)— (inverse            caprolactone ester moiety), —O(CH₂)_(m)C(═O)—, or            —O(CH₂CH₂O)_(n)OCH₂C(═O)—;    -   each Y¹ is independently:        -   —C(═O)CH₂O— (glycolic ester moiety), —C(═O)CH(CH₃)O— (lactic            ester moiety), —C(═O)CH₂OCH₂CH₂O— (dioxanone ester moiety),            —C(═O)CH₂CH₂CH₂CH₂CH₂O— (caprolactone ester moiety),            —C(═O)(CH₂)_(m)O—, or —C(═O)CH₂O(CH₂CH₂O)_(n)—;    -   R is a di-, tri, tetra-, penta- or hexaradical derived from        C₁₋₂₅ alkyl, aryl, or aryl-(C₁₋₆alkyl)₁₋₃-, wherein from 1-4 of        the CH₂ groups, preferably 1-3 of the CH₂ groups, within the        alkyl chain are optionally independently replaced by O or S        atoms, preferably by O atoms, such that each of said O or S        atoms is attached only to carbon atoms in the alkyl chain, with        the proviso that the O or S atoms are separated from the di-,        tri, tetra-, penta- or hexaradical chain ends by at least one        carbon atom and that multiple O or S atoms in the di-, tri,        tetra-, penta- or hexaradical chain must be separated from each        other by at least two carbon atoms; or R is —[CH₂CH₂O—]_(p)—,        wherein p is an integer from about 10 to about 50;    -   each a and b is independently an integer from about 0 to about        6;    -   each m, n, y, and z is independently an integer from about 2 to        about 24;    -   w is an integer from about 2 to about 6; and    -   c and d are each an integer from 1 to 5, with the proviso that        the sum of c+d is an integer from about 2 to about 6.

In another aspect, the present invention provides absorbable polymers.In certain aspects, these polymers are useful for wound closure devicesand application such as sutures, staples, clips, adhesion preventionbarriers, and tissue adhesives with controlled degradation profiles, aswell as other biomedical devices.

In another aspect, the present invention provides cross-linked hydrogelsfor drug delivery with controlled degradation profiles.

In another aspect, the present invention is directed to compounds offormula Iva:R^(4a)—O—(Y^(1a))_(c)—O—(Y^(a))_(d)—O—R^(4a)  IVa

wherein:

-   -   each Y^(1a) is independently:        -   —C(═O)CH₂O—, —C(═O)CH(CH₃)O—, —C(═O)CH₂OCH₂CH₂O—,            —C(═O)CH₂CH₂CH₂CH₂CH₂O—, —C(═O)(CH₂)_(m)O—, or            —C(═O)CH₂O(CH₂CH₂O)_(n)—;    -   each Y^(a) is independently:        -   —OCH₂C(═O)—, —OCH(CH₃)C(═O)—, —OCH₂CH₂OCH₂C(═O)—,            —OCH₂CH₂CH₂CH₂CH₂C(═O)—, —O(CH₂)_(m)C(═O)—, or            —O(CH₂CH₂O)_(n)—OCH₂C(═O)—;    -   each R^(4a) is independently H, alkyl, or aralkyl;    -   each m and n is independently an integer from about 2 to about        24; and    -   c and d are each an integer from 1 to 5, with the proviso that        the sum of c+d is an integer from about 2 to about 6.

In some other aspects, the present invention is directed to linkers orpharmaceutically acceptable salts thereof of formula Iz, IIz, IIIz, IVz,or Vz:R[—C(═O)—(Y)_(a)—O—R^(1b)]_(w)  IzR[—(X)_(a)—OC(═O)—R^(2b)]_(w)  IIzR[—(Y)_(a)—O—R^(3b)]_(w)  IIIzR⁴—O—(Y¹)_(c)—O—(Y)_(d)—O—R^(4b)  IVzR[—(X)_(a)—O—R^(5b)]_(w)  Vz

wherein:

-   -   each —O—R^(1b), —O—R^(3b), —O—R^(4b), R^(4b)—O—, and —O—R^(5b)        is independently:

-   -   each —OC(═O)—R^(2b) is independently:

-   -   each Z is independently: NH₂, NH(Y¹)_(b)H, N((X¹)_(b)H)₂, NCO,        CH₂CO₂H, or CH═CHCO₂H;    -   each X is independently:        -   —OC(═O)CH₂— (inverse glycolic acid moiety), —OC(═O)CH(CH₃)—            (inverse lactic acid moiety), —OC(═O)CH₂OCH₂CH₂— (inverse            dioxanone acid moiety), —OC(═O)CH₂CH₂CH₂CH₂CH₂— (inverse            caprolactone acid moiety), —OC(═O)(CH₂)_(y)—, or            —OC(═O)CH₂(OCH₂CH₂)_(z)—.    -   each X¹ is independently:        -   —CH₂C(═O)O— (glycolic acid moiety), —CH(CH₃)C(═O)O— (lactic            acid moiety), —CH₂CH₂OCH₂C(═O)O— (dioxanone acid moiety),            —CH₂CH₂CH₂CH₂CH₂C(═O)O— (caprolactone acid moiety),            —(CH₂)_(y)C(═O)O—, or —(CH₂CH₂O)_(z)CH₂C(═O)O—;    -   each Y is independently:        -   —OCH₂C(═O)— (inverse glycolic ester moiety), —OCH(CH₃)C(═O)—            (inverse lactic ester moiety), —OCH₂CH₂OCH₂C(═O)— (inverse            dioxanone ester moiety), —OCH₂CH₂CH₂CH₂CH₂C(═O)— (inverse            caprolactone ester moiety), —O(CH₂)_(m)C(═O)—, or            —O(CH₂CH₂O)_(n)OCH₂C(═O)—;    -   each Y¹ is independently:        -   —C(═O)CH₂O— (glycolic ester moiety), —C(═O)CH(CH₃)O— (lactic            ester moiety), —C(═O)CH₂OCH₂CH₂O— (dioxanone ester moiety),            —C(═O)CH₂CH₂CH₂CH₂CH₂O— (caprolactone ester moiety),            —C(═O)(CH₂)_(m)O—, or —C(═O)CH₂O(CH₂CH₂O)_(n)—;    -   R is a di-, tri, tetra-, penta- or hexaradical derived from        C₁₋₂₅ alkyl, aryl, or aryl-(C₁₋₆alkyl)₁₋₃-, wherein from 1-3 of        the CH₂ groups within the alkyl chain are optionally        independently replaced by O or S atoms, such that each of said O        or S atoms is attached only to carbon atoms in the alkyl chain,        with the proviso that multiple heteroatoms must be separated        from each other and from the di-, tri, tetra-, penta- or        hexaradical chain ends by at least one carbon atom; or R is        —[CH₂CH₂O—]_(p)—, wherein p is an integer from about 10 to about        50;    -   each a and b is independently an integer from about 1 to about        6;    -   each m, n, y, and z is independently an integer from about 2 to        about 24;    -   w is an integer from about 2 to about 6; and    -   c and d are each an integer from 1 to 5, with the proviso that        the sum of c+d is an integer from about 2 to about 6.

In certain other aspects, the present invention is directed to compoundsof formula Iz, IIz, IIIz, IVz, or Vz:R[—C(═O)—(Y)_(a)—O—R^(1b)]_(w)  IzR[—(X)_(a)—OC(═O)—R^(2b)]_(w)  IIzR[—(Y)_(a)—O—R^(3b)]_(w)  IIIzR^(4b)—O—(Y¹)_(c)—O—(Y)_(d)—O—R^(4b)  IVzR[—(X)_(a)—O—R^(5b)]_(w)  Vz

wherein:

-   -   each R^(1b), R^(2b), R^(3b), R^(4b), and R^(5b) is independently        H, alkyl, or aralkyl;    -   each Z is independently: NH₂, NH(Y¹)_(b)H, N((X¹)_(b)H)₂, NCO,        CH₂CO₂H, or CH═CHCO₂H;    -   each X is independently:        -   —OC(═O)CH₂— (inverse glycolic acid moiety), —OC(═O)CH(CH₃)—            (inverse lactic acid moiety), —OC(═O)CH₂OCH₂CH₂— (inverse            dioxanone acid moiety), —OC(═O)CH₂CH₂CH₂CH₂CH₂— (inverse            caprolactone acid moiety), —OC(═O)(CH₂)_(y)—, or            —OC(═O)CH₂(OCH₂CH₂)_(z)—.    -   each X¹ is independently:        -   —CH₂C(═O)O— (glycolic acid moiety), —CH(CH₃)C(═O)O— (lactic            acid moiety), —CH₂CH₂OCH₂C(═O)O— (dioxanone acid moiety),            —CH₂CH₂CH₂CH₂CH₂C(═O)O— (caprolactone acid moiety),            —(CH₂)_(y)C(═O)O—, or —(CH₂CH₂O)_(z)CH₂C(═O)O—;    -   each Y is independently:        -   —OCH₂C(═O)— (inverse glycolic ester moiety), —OCH(CH₃)C(═O)—            (inverse lactic ester moiety), —OCH₂CH₂OCH₂C(═O)— (inverse            dioxanone ester moiety), —OCH₂CH₂CH₂CH₂CH₂C(═O)— (inverse            caprolactone ester moiety), —O(CH₂)_(m)C(═O)—, or            —O(CH₂CH₂O)_(n)OCH₂C(═O)—;    -   each Y¹ is independently:        -   —C(═O)CH₂O— (glycolic ester moiety), —C(═O)CH(CH₃)O— (lactic            ester moiety), —C(═O)CH₂OCH₂CH₂O— (dioxanone ester moiety),            —C(═O)CH₂CH₂CH₂CH₂CH₂O— (caprolactone ester moiety),            —C(═O)(CH₂)_(m)O—, or —C(═O)CH₂O(CH₂CH₂O)_(n)—;    -   R is a di-, tri, tetra-, penta- or hexaradical derived from        C₁₋₂₅ alkyl, aryl, or aryl-(C₁₋₆alkyl)₁₋₃-, wherein from 1-3 of        the CH₂ groups within the alkyl chain are optionally        independently replaced by O or S atoms, such that each of said O        or S atoms is attached only to carbon atoms in the alkyl chain,        with the proviso that multiple heteroatoms must be separated        from each other and from the di-, tri, tetra-, penta- or        hexaradical chain ends by at least one carbon atom; or R is        —[CH₂CH₂O—]_(p)—, wherein p is an integer from about 10 to about        50;    -   each a and b is independently an integer from about 1 to about        6;    -   each m, n, y, and z is independently an integer from about 2 to        about 24;    -   w is an integer from about 2 to about 6; and    -   c and d are each an integer from 1 to 5, with the proviso that        the sum of c+d is an integer from about 2 to about 6.

In certain aspects of the invention, these compounds are useful asintermediates in the preparation of the linkers of the presentinvention, and/or polymers derived therefrom.

These and other objects, which will become apparent during the followingdetailed description, have been achieved by the inventors' discoverythat the presently claimed linkers are useful for forming tunablebiodegradable polymers.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to the discovery of new class of linearand multiarmed hydrolysable linkers and cross linkers respectively forapplications including the synthesis of biodegradable polymers such aspolyesters, polyurethanes, polyamides, polyureas, and degradable epoxyamine resin. The linear and multiarmed hydrolysable linkers of thepresent invention include symmetrical and/or unsymmetrical ethercarboxylic acids, amines, amide diols, amine polyols, and isocyanates.In certain embodiments of the present invention, the application ofthese linkers and crosslinkers during synthesis may result inbiodegradable polymers with controlled degradation profiles.

More particularly, the present invention described herein providesbiologically-acceptable and biodegradable linear and multiarmed linkersand cross-linkers with tunable degradation profiles, preferably usingmethods of stepwise synthesis of the degradable region, which results inpurer compounds at the end of the synthetic sequence. The syntheticsequence, in many instances, and the resulting purity of the linkersleads to reaction products that are also readily purifiable.

While not wishing to be bound by theory, Applicants believe that thelength of the degradable region is a major structural determinant of thedegradation rate. Thus, in certain embodiments, the present inventionprovides a controlled degradation rate. By varying the functionalizingmoiety or combination of moieties, the rate of biodegradation may bevaried over a period of time, for example, from about one month to aboutfour years, and may be selected as desired, depending on the end-use.

Applicants have discovered that the invention described herein isapplicable to hydrophobic networks as well as hydrophilic networks. Insome embodiments, rapid degradation rate and water solubility throughthe incorporation of oligomeric cross-linking compounds of the presentinvention are among the useful physical and/or chemical properties thatare attainable without resorting to polymeric cross-linking compounds.

Accordingly, in some embodiments, the present invention provides novellinear and multiarmed hydrolysable monomeric and/or oligomeric linkers,or pharmaceutically acceptable salts thereof of formulas I, II, III, orIV:R[—C(═O)—(Y)_(a)—O—R¹]_(w)  IR[—(X)_(a)—OC(═O)—R²]_(w)  IIR[—(Y)_(a)—O—R³]_(w)  IIIR⁴—O—(Y¹)_(c)—O—(Y)_(d)—O—R⁴  IV

wherein:

-   -   each —O—R¹, —O—R³, —O—R⁴, and R⁴—O— is independently:

-   -   each —OC(═O)—R² is independently:

-   -   each Z is independently: NH₂, NH(Y¹)_(b)H, N((X¹)_(b)H)₂, NCO,        CH₂CO₂H, or CH═CHCO₂H;    -   each X is independently:        -   —OC(═O)CH₂— (inverse glycolic acid moiety), —OC(═O)CH(CH₃)—            (inverse lactic acid moiety), —OC(═O)CH₂OCH₂CH₂— (inverse            dioxanone acid moiety), —OC(═O)CH₂CH₂CH₂CH₂CH₂— (inverse            caprolactone acid moiety), —OC(═O)(CH₂)_(y)—, or            —OC(═O)CH₂(OCH₂CH₂)_(z)—.    -   each X¹ is independently:        -   —CH₂C(═O)O— (glycolic acid moiety), —CH(CH₃)C(═O)O— (lactic            acid moiety), —CH₂CH₂OCH₂C(═O)O— (dioxanone acid moiety),            —CH₂CH₂CH₂CH₂CH₂C(═O)O— (caprolactone acid moiety),            —(CH₂)_(y)C(═O)O—, or —(CH₂CH₂O)_(z)CH₂C(═O)O—;    -   each Y is independently:        -   —OCH₂C(═O)— (inverse glycolic ester moiety), —OCH(CH₃)C(═O)—            (inverse lactic ester moiety), —OCH₂CH₂OCH₂C(═O)— (inverse            dioxanone ester moiety), —OCH₂CH₂CH₂CH₂CH₂C(═O)— (inverse            caprolactone ester moiety), —O(CH₂)_(m)C(═O)—, or            —O(CH₂CH₂O)_(n)OCH₂C(═O)—;    -   each Y¹ is independently:        -   —C(═O)CH₂O— (glycolic ester moiety), —C(═O)CH(CH₃)O— (lactic            ester moiety), —C(═O)CH₂OCH₂CH₂O— (dioxanone ester moiety),            —C(═O)CH₂CH₂CH₂CH₂CH₂O— (caprolactone ester moiety),            —C(═O)(CH₂)_(m)O—, or —C(═O)CH₂O(CH₂CH₂O)_(n)—;    -   R is a di-, tri, tetra-, penta- or hexaradical derived from        C₁₋₂₅ alkyl, aryl, or aryl-(C₁₋₆alkyl)₁₋₃-, wherein from 1-4 of        the CH₂ groups, preferably 1-3 of the CH₂ groups, within the        alkyl chain are optionally independently replaced by O or S        atoms, preferably by O atoms, such that each of said O or S        atoms is attached only to carbon atoms in the alkyl chain, with        the proviso that the O or S atoms are separated from the di-,        tri, tetra-, penta- or hexaradical chain ends by at least one        carbon atom and that multiple O or S atoms in the di-, tri,        tetra-, penta- or hexaradical chain must be separated from each        other by at least two carbon atoms; or R is —[CH₂CH₂O—]_(p)—,        wherein p is an integer from about 10 to about 50;    -   each a and b is independently an integer from about 0 to about        6;    -   each m, n, y, and z is independently an integer from about 2 to        about 24;    -   w is an integer from about 2 to about 6; and    -   c and d are each an integer from 1 to 5, with the proviso that        the sum of c+d is an integer from about 2 to about 6.

In some other embodiments, the present invention is directed to linkersor pharmaceutically acceptable salts thereof of formula Iz, IIz, IIIz,IVz, or Vz:R[—C(═O)—(Y)_(a)—O—R^(1b)]_(w)  IzR[—(X)_(a)—OC(═O)—R^(2b)]_(w)  IIzR[—(Y)_(a)—O—R^(3b)]_(w)  IIIzR⁴—O—(Y¹)_(c)—O—(Y)_(d)—O—R^(4b)  IVzR[—(X)_(a)—O—R^(5b)]_(w)  Vz

wherein:

-   -   each —O—R^(1b), —O—R^(3b), —O—R^(4b), R^(4b)—O—, and —O—R^(5b)        is independently:

-   -   each —OC(═O)—R^(2b) is independently:

-   -   each Z is independently: NH₂, NH(Y¹)_(b)H, N((X¹)_(b)H)₂, NCO,        CH₂CO₂H, or CH═CHCO₂H;    -   each X is independently:        -   —OC(═O)CH₂— (inverse glycolic acid moiety), —OC(═O)CH(CH₃)—            (inverse lactic acid moiety), —OC(═O)CH₂OCH₂CH₂— (inverse            dioxanone acid moiety), —OC(═O)CH₂CH₂CH₂CH₂CH₂— (inverse            caprolactone acid moiety), —OC(═O)(CH₂)_(y)—, or            —OC(═O)CH₂(OCH₂CH₂)_(z)—.    -   each X¹ is independently:        -   —CH₂C(═O)O— (glycolic acid moiety), —CH(CH₃)C(═O)O— (lactic            acid moiety), —CH₂CH₂OCH₂C(═O)O— (dioxanone acid moiety),            —CH₂CH₂CH₂CH₂CH₂C(═O)O— (caprolactone acid moiety),            —(CH₂)_(y)C(═O)O—, or —(CH₂CH₂O)_(z)CH₂C(═O)O—;    -   each Y is independently:        -   —OCH₂C(═O)— (inverse glycolic ester moiety), —OCH(CH₃)C(═O)—            (inverse lactic ester moiety), —OCH₂CH₂OCH₂C(═O)— (inverse            dioxanone ester moiety), —OCH₂CH₂CH₂CH₂CH₂C(═O)— (inverse            caprolactone ester moiety), —O(CH₂)_(m)C(═O)—, or            —O(CH₂CH₂O)_(n)OCH₂C(═O)—;    -   each Y¹ is independently:        -   —C(═O)CH₂O— (glycolic ester moiety), —C(═O)CH(CH₃)O— (lactic            ester moiety), —C(═O)CH₂OCH₂CH₂O— (dioxanone ester moiety),            —C(═O)CH₂CH₂CH₂CH₂CH₂O— (caprolactone ester moiety),            —C(═O)(CH₂)_(m)O—, or —C(═O)CH₂O(CH₂CH₂O)_(n)—;    -   R is a di-, tri, tetra-, penta- or hexaradical derived from        C₁₋₂₅ alkyl, aryl, or aryl-(C₁₋₆alkyl)₁₋₃-, wherein from 1-3 of        the CH₂ groups within the alkyl chain are optionally        independently replaced by O or S atoms, such that each of said O        or S atoms is attached only to carbon atoms in the alkyl chain,        with the proviso that multiple heteroatoms must be separated        from each other and from the di-, tri, tetra-, penta- or        hexaradical chain ends by at least one carbon atom; or R is        —[CH₂CH₂O—]_(p)—, wherein p is an integer from about 10 to about        50;    -   each a and b is independently an integer from about 1 to about        6;    -   each m, n, y, and z is independently an integer from about 2 to        about 24;    -   w is an integer from about 2 to about 6; and    -   c and d are each an integer from 1 to 5, with the proviso that        the sum of c+d is an integer from about 2 to about 6.

In certain other embodiments, the present invention is directed tocompounds of formula Iz, IIz, IIIz, IVz, or Vz:R[—C(═O)—(Y)_(a)—O—R^(1b)]_(w)  IzR[—(X)_(a)—OC(═O)—R^(2b)]_(w)  IIzR[—(Y)_(a)—O—R^(3b)]_(w)  IIIzR^(4b)—O—(Y¹)_(c)—O—(Y)_(d)—O—R^(4b)  IVzR[—(X)_(a)—O—R^(5b)]_(w)  Vz

wherein:

-   -   each R^(1b), R^(2b), R^(3b), R^(4b), and R^(5b) is independently        H, alkyl, or aralkyl;    -   each Z is independently: NH₂, NH(Y¹)_(b)H, N((X¹)_(b)H)₂, NCO,        CH₂CO₂H, or CH═CHCO₂H;    -   each X is independently:        -   —OC(═O)CH₂— (inverse glycolic acid moiety), —OC(═O)CH(CH₃)—            (inverse lactic acid moiety), —OC(═O)CH₂OCH₂CH₂— (inverse            dioxanone acid moiety), —OC(═O)CH₂CH₂CH₂CH₂CH₂— (inverse            caprolactone acid moiety), —OC(═O)(CH₂)_(y)—, or            —OC(═O)CH₂(OCH₂CH₂)_(z)—.    -   each X¹ is independently:        -   —CH₂C(═O)O— (glycolic acid moiety), —CH(CH₃)C(═O)O— (lactic            acid moiety), —CH₂CH₂OCH₂C(═O)O— (dioxanone acid moiety),            —CH₂CH₂CH₂CH₂CH₂C(═O)O— (caprolactone acid moiety),            —(CH₂)_(y)C(═O)O—, or —(CH₂CH₂O)_(z)CH₂C(═O)O—;    -   each Y is independently:        -   —OCH₂C(═O)— (inverse glycolic ester moiety), —OCH(CH₃)C(═O)—            (inverse lactic ester moiety), —OCH₂CH₂OCH₂C(═O)— (inverse            dioxanone ester moiety), —OCH₂CH₂CH₂CH₂CH₂C(═O)— (inverse            caprolactone ester moiety), —O(CH₂)_(m)C(═O)—, or            —O(CH₂CH₂O)_(n)OCH₂C(═O)—;    -   each Y¹ is independently:        -   —C(═O)CH₂O— (glycolic ester moiety), —C(═O)CH(CH₃)O— (lactic            ester moiety), —C(═O)CH₂OCH₂CH₂O— (dioxanone ester moiety),            —C(═O)CH₂CH₂CH₂CH₂CH₂O— (caprolactone ester moiety),            —C(═O)(CH₂)_(m)O—, or —C(═O)CH₂O(CH₂CH₂O)_(n)—;    -   R is a di-, tri, tetra-, penta- or hexaradical derived from        C₁₋₂₅ alkyl, aryl, or aryl-(C₁₋₆alkyl)₁₋₃-, wherein from 1-3 of        the CH₂ groups within the alkyl chain are optionally        independently replaced by O or S atoms, such that each of said O        or S atoms is attached only to carbon atoms in the alkyl chain,        with the proviso that multiple heteroatoms must be separated        from each other and from the di-, tri, tetra-, penta- or        hexaradical chain ends by at least one carbon atom; or R is        —[CH₂CH₂O—]_(p)—, wherein p is an integer from about 10 to about        50;    -   each a and b is independently an integer from about 1 to about        6;    -   each m, n, y, and z is independently an integer from about 2 to        about 24;    -   w is an integer from about 2 to about 6; and    -   c and d are each an integer from 1 to 5, with the proviso that        the sum of c+d is an integer from about 2 to about 6.

In some preferred embodiments of linkers or pharmaceutically acceptablesalts thereof of the present invention, the linkers or pharmaceuticallyacceptable salts thereof have formula II or IIz. In alternativelypreferred embodiments, the linkers or pharmaceutically acceptable saltsthereof have formula IV or IVz.

In certain preferred embodiments, the linkers or pharmaceuticallyacceptable salts thereof of formulas I, II, or III, have formulas Ia-f,IIa-h, and IIa-f respectively:(—CH₂—)[C(═O)—(Y)_(a)—O—R¹]₂  Ia;(—CH₂CH₂—)[C(═O)—(Y)_(a)—O—R¹]₂  Ib;(—CH₂CH₂CH₂—)[C(═O)—(Y)_(a)—O—R¹]₂  Ic;(—CH₂CH₂CH₂CH₂—)[C(═O)—(Y)_(a)—O—R¹]₂  Id(—CH₂CH₂—O—CH₂CH₂—)[C(═O)—(Y)_(a)—O—R¹]₂  Ie;[—O(—CH₂CH₂—O—)_(p)][C(═O)—(Y)_(a)—O—R¹]₂  If;(—CH₂—)[(X)_(a)—OC(═O)—R²]₂  IIa;(—CH₂CH₂—)[(X)_(a)—OC(═O)—R²]₂  IIb;(—CH₂CH₂CH₂—)[(X)_(a)—OC(═O)—R²]₂  IIc;(—CH₂CH₂CH₂CH₂—)[(X)_(a)—OC(═O)—R²]₂  IId;(—CH₂CH₂—O—CH₂CH₂—)[(X)_(a)—OC(═O)—R²]₂  IIe;(>C(H)—)[(X)_(a)—OC(═O)—R²]₃  IIf;(>C(CH₂CH₃)—)[(X)_(a)—OC(═O)—R²]₃  IIg;(>C<)[(X)_(a)—OC(═O)—R²]₄  IIh;(—CH₂—)[—(Y)_(a)—O—R³]₂  IIIa;(—CH₂CH₂—)[—(Y)_(a)—O—R³]₂  IIIb;(—CH₂CH₂CH₂—)[—(Y)_(a)—O—R³]₂  IIIc;(—CH₂CH₂CH₂CH₂—)[—(Y)_(a)—O—R³]₂  IIId;(—CH₂CH₂—O—CH₂CH₂—)[—(Y)_(a)—O—R³]₂  IIIe; or[—O(—CH₂CH₂—O—)_(p)][—(Y)_(a)—O—R³]₂  IIIf.

In certain other preferred embodiments, the linkers or pharmaceuticallyacceptable salts thereof of formulas Iz, IIz, or IIIz, have formulasIa₁-f₁, IIa₁-h₁, and IIa₁-f₁ respectively:(—CH₂—)[C(═O)—(Y)_(a)—O—R¹]₂  Ia₁;(—CH₂CH₂—)[C(═O)—(Y)_(a)—O—R¹]₂  Ib₁;(—CH₂CH₂CH₂—)[C(═O)—(Y)_(a)—O—R¹]₂  Ic₁;(—CH₂CH₂CH₂CH₂—)[C(═O)—(Y)_(a)—O—R¹]₂  Id₁(—CH₂CH₂—O—CH₂CH₂—)[C(═O)—(Y)_(a)—O—R¹]₂  Ie₁;[—O(—CH₂CH₂—O—)_(p)][C(═O)—(Y)_(a)—O—R¹]₂  If₁;(—CH₂—)[(X)_(a)—OC(═O)—R²]₂  IIa₁;(—CH₂CH₂—)[(X)_(a)—OC(═O)—R²]₂  IIb₁;(—CH₂CH₂CH₂—)[(X)_(a)—OC(═O)—R²]₂  IIc₁;(—CH₂CH₂CH₂CH₂—)[(X)_(a)—OC(═O)—R^(2b)]₂  IId₁;(—CH₂CH₂—O—CH₂CH₂—)[(X)_(a)—OC(═O)—R^(2b)]₂  IIe₁;(>C(H)—)[(X)_(a)—OC(═O)—R^(2b)]₃  IIf₁;(>C(CH₂CH₃)—)[(X)_(a)—OC(═O)—R^(2b)]₃  IIg₁;(>C<)[(X)_(a)—OC(═O)—R^(2b)]₄  IIh₁;(—CH₂—)[—(Y)_(a)—O—R^(3b)]₂  IIIa₁;(—CH₂CH₂—)[—(Y)_(a)—O—R^(3b)]₂  IIIb₁;(—CH₂CH₂CH₂—)[—(Y)_(a)—O—R^(3b)]₂  IIIc₁;(—CH₂CH₂CH₂CH₂—)[—(Y)_(a)—O—R^(3b)]₂  IIId₁;(—CH₂CH₂—O—CH₂CH₂—)[—(Y)_(a)—O—R^(3b)]₂  IIIe₁; or[—O(—CH₂CH₂—O—)_(p)][—(Y)_(a)—O—R^(3b)]₂  IIIf₁.

In certain preferred aspects of compounds, linkers or pharmaceuticallyacceptable salts thereof of formulas I, Iz, Ia₁-f₁, Ia-f, II, IIz,IIa₁-h₁, IIa-h, III, IIIz, IIIa₁-f₁, IIIa-f, IV, IVz, or Vz, themoieties X, X¹, Y, and/or Y¹ are each independently attached in thelinkers by ester and/or ether linkages.

In compounds, linkers or pharmaceutically acceptable salts thereof offormula IV, the O between the two Y groups depicted as (Y¹)—O—(Y)represents an ether linkage between the Y and Y¹ groups such that thereis only one —O— ether moiety in the chain (Y)—O—(Y¹). By way of example,when Y¹ is corresponds to —C(═O)CH₂O— (glycolic ester moiety), and Ycorresponds to —OCH(CH₃)C(═O)— (inverse lactic ester moiety), theresultant (Y¹)—O—(Y) is —C(═O)CH₂O—CH(CH₃)C(═O)—. Similarly, when R is—[CH₂CH₂O—]_(p)— and is connected to (Y), the resultant R—(Y) is—[CH₂CH₂O—]_(p)—CH(CH₃)C(═O)—, when for example, (Y¹) is—OCH(CH₃)C(═O)—.

In some preferred embodiments of compounds, linkers or pharmaceuticallyacceptable salts thereof of formula I, Iz, Ia₁-f₁, Ia-f, III, IIIz,IIIa₁-f₁, IIIa-f, IV, or IVz, Y and Y¹ are derived from differenthydroxyacid or lactone precursors. As non-limiting examples, Y may be—OCH(CH₃)C(═O)— (derived from lactic acid) and Y¹ may be —C(═O)CH₂O—(derived from glycolic acid), or Y may be derived from glycolic acid andY¹ may be derived from caprolactone.

In some preferred embodiments of compounds, linkers or pharmaceuticallyacceptable salts thereof of formula II, IIz, IIa₁-h₁, IIa-h, or Vz, Xand X¹ are derived from different hydroxyacid or lactone precursors. Asnon-limiting examples, X may be —OC(═O)CH(CH₃)— (derived from lacticacid) and X¹ may be —CH₂C(═O)O— (derived from glycolic acid), or X maybe derived from glycolic acid and X¹ may be derived from caprolactone.

In other preferred embodiments of compounds, linkers or pharmaceuticallyacceptable salts thereof of formulas I, Iz, Ia₁-f₁, Ia-f, II, IIz,IIa₁-h₁, IIa-h, III, IIIz, IIIa₁-f₁, IIIa-f, IV, IVz, or Vz, R is a di-,tri, tetra-, penta- or hexaradical derived from C₁₋₂₅ alkyl, aryl,preferably phenyl, or aryl-(C₁₋₆alkyl)₁₋₃-, preferably phenyl-(C₁₋₆alkyl)₁₋₃-. Whether R is a di-, tri, tetra-, penta- or hexaradical isdetermined by w. For example, when w is 2, R is a diradical; when w is4, R is a tetraradical, and so forth. In certain preferred embodimentswherein R is derived from C₁₋₂₅ alkyl or aryl-(C₁₋₆ alkyl)₁₋₃-, 1-4 ofthe CH₂ groups, preferably 1-3 of the CH₂ groups, within the alkyl chainare optionally independently replaced by O or S atoms, preferably by Oatoms, such that each of said O or S atoms is attached only to carbonatoms in the alkyl chain, preferably with the proviso that the O or Satoms are separated from the di-, tri, tetra-, penta- or hexaradicalchain ends by at least one carbon atom and that multiple O or S atoms inthe diradical chain must be separated from each other by at least twocarbon atoms. Alternatively in some preferred embodiments, when R isalkyl, it is more preferably (CH₂), (CH₂)₃, CH(CH₂)₃, C(CH₂)₄, orC(CH₂CH₃)(CH₂)₃. In still other preferred embodiments, R is (CH₂)₃, andwherein the C-2 CH₂ group within the (CH₂)₃ chain is optionally replacedby an O atom. In yet other preferred embodiments, R is (CH₂)₂, (CH₂)₃,(CH₂)₄, (CH₂OCH₂), or (CH₂CH₂OCH₂CH₂). In still other preferredembodiments, R is (CH₂CHCH₂) when w is 3, or (C(CH₂)₄) when w is 4.

Alternatively, R is —[CH₂CH₂O—]_(p)—, wherein p is an integer from about10 to about 50, preferably from about 10 to about 30, more preferablyfrom about 10 to about 20. As used herein for linear and multiarmedhydrolysable linkers and cross linkers of formulas I, II, or III, when Ris —[CH₂CH₂O—]_(p)—, the two oxygen atoms in the moiety “O—R—O” areimplicit in the R moiety. For example, the terminal oxygen atoms in thediradical —O—CH₂CH₂—O—CH₂CH₂—O— (that is, wherein R is —[CH₂CH₂O—]_(p)—and p is 2) form part of both the R and the two “O” atom functions. Thuswhen R is —[CH₂CH₂O—]_(p)— and p is 2) the hydrolysable linkers offormula II have the formula:R²—C(═O)O—(X¹)_(a)—O—CH₂CH₂—O—CH₂CH₂—O—(X)_(a)—OC(═O)—R².

As used herein, the term “aryl-(C₁₋₆ alkyl)₁₋₃-” refers to a aryl ring,preferably a benzene ring, having 1 to 3 pendant alkyl groups, whereinthe aryl-(C₁₋₆ alkyl)₁₋₃-, preferably phenyl-(C₁₋₆ alkyl)₁₋₃-moiety, isattached to the remainder of the structure in a given formula throughits pendant alkyl group(s).

In certain embodiments of compounds, linkers or pharmaceuticallyacceptable salts thereof of the invention, such as for example formulasI, Iz, Ia₁-f₁, Ia-f, II, IIz, IIa₁-h₁, IIa-h, III, IIIz, IIIa₁-f₁,IIIa-f, or Vz, each a is independently an integer from about 0 to about6, preferably wherein at least one a is an integer from 1 to about 6,more preferably from 1 to about 3. Alternatively preferred, each a isindependently an integer from about 1 to about 6, preferably from 1 toabout 3, with from 1 to about 2 being even more preferred.

In some other embodiments of compounds, linkers or pharmaceuticallyacceptable salts thereof of the invention, such as for example formulasI, Iz, Ia₁-f₁, Ia-f, II, IIz, IIa₁-h₁, IIa-h, III, IIIz, IIIa₁-f₁,IIIa-f, IV, IVz, or Vz, each b is independently an integer from about 0to about 6, preferably wherein at least one b is an integer from 1 toabout 6, more preferably from 1 to about 3. Alternatively preferred,each b is independently an integer from about 1 to about 6, preferablyfrom 1 to about 3, with from 1 to about 2 being even more preferred.

In certain other preferred embodiments of compounds, linkers orpharmaceutically acceptable salts thereof of formulas I, Iz, Ia₁-f₁,Ia-f, II, IIz, IIa₁-h₁, IIa-h, III, IIIz, IIIa₁-f₁, IIIa-f, or Vz, w isan integer from about 2 to about 4.

In certain preferred embodiments of compounds, linkers orpharmaceutically acceptable salts thereof of the invention, c and d areeach 1, 2, or 3; more preferably both c and d are 1, or they are both 2,or they are both 3.

In still other preferred embodiments of compounds, linkers orpharmaceutically acceptable salts thereof of formula II, IIz, IIa₁-h₁,or IIa-h, each X is independently —OC(═O)CH₂—, —OC(═O)CH(CH₃)—,—OC(═O)CH₂OCH₂CH₂—, or —OC(═O)CH₂CH₂CH₂CH₂CH₂—; more preferably—OC(═O)CH₂— or —OC(═O)CH(CH₃)—.

In some other preferred embodiments of compounds, linkers orpharmaceutically acceptable salts thereof of formulas II, IIz, IIa₁-h₁,or IIa-h, each X¹ is independently —CH₂C(═O)O—, —CH(CH₃)C(═O)O—,—CH₂CH₂OCH₂C(═O)O—, or —CH₂CH₂CH₂CH₂CH₂C(═O)O—, more preferably—CH₂C(═O)O— or —CH(CH₃)C(═O)O—.

In some preferred embodiments of compounds, linkers or pharmaceuticallyacceptable salts thereof of formulas I, Iz, Ia₁-f₁, Ia-f, III, IIIz,IIIa₁-f₁, IIIa-f, IV, or IVz, each Y is independently —OCH₂C(═O)—,—OCH(CH₃)C(═O)—, —OCH₂CH₂OCH₂C(═O)—, or —OCH₂CH₂CH₂CH₂CH₂C(═O)—, morepreferably —OCH₂C(═O)— or —OCH(CH₃)C(═O)—.

In certain preferred embodiments of compounds, linkers orpharmaceutically acceptable salts thereof of formula I, Iz, Ia₁-f₁,Ia-f, II, IIz, IIa₁-h₁, IIa-h, III, IIIz, IIIa₁-f₁, IIIa-f, IV, or IVz,each Y¹ is independently —C(═O)CH₂O—, —C(═O)CH(CH₃)O—,—C(═O)CH₂OCH₂CH₂O—, or —C(═O)CH₂CH₂CH₂CH₂CH₂O—; more preferably—C(═O)CH₂O— or —C(═O)CH(CH₃)O—.

Certain embodiments of the invention are directed to linkers orpharmaceutically acceptable salts thereof of formula I, Iz, II, IIz,III, IIIz, IV, IVz, or Vz having a Z-substituted phenyl ring, whereinthe Z moiety is present as a substituent on the phenyl ring of R¹, R²,R³, or R⁴. The ring position of the Z moiety in relation to the oxy orcarboxy group also attached to the phenyl ring is not critical, and maybe located ortho, meta, or para to the carboxy group of R² or the oxygroup of R¹, R³, or R⁴. Preferably, Z is positioned meta or para, morepreferably para to said carboxy or oxy group.

Other embodiments of the present invention are directed to polyesters ofthe formula:

wherein:

-   -   each Y^(1f) is independently —C(═O)CH₂O—, —C(═O)CH(CH₃)O—,        —C(═O)CH₂OCH₂CH₂O—, —C(═O)CH₂CH₂CH₂CH₂CH₂O—, —C(═O)(CH₂)_(m)O—,        or —C(═O)CH₂O(CH₂CH₂O)_(n)—;    -   each Y^(f) is independently —OCH₂C(═O)—, —OCH(CH₃)C(═O)—,        —OCH₂CH₂OCH₂C(═O)—, —OCH₂CH₂CH₂CH₂CH₂C(═O)—, —O(CH₂)_(m)C(═O)—,        or —O(CH₂CH₂O)_(n)OCH₂C(═O)—;    -   each m and n is independently an integer from about 2 to about        24;    -   k¹ is an integer from about 100 to about 5000; and    -   each k^(2a) and k^(2b) is independently 1 to about 5.

In some preferred embodiments of the polyesters of the presentinvention, Y^(f) and Y^(1f) are derived from different hydroxyacid orlactone precursors. As non-limiting examples, Y^(f) may be—OCH(CH₃)C(═O)— (derived from lactic acid) and Y^(1f) may be —C(═O)CH₂O—(derived from glycolic acid), or Y^(f) may be derived from glycolic acidand Y^(1f) may be derived from caprolactone.

In certain preferred embodiments of the polyesters of the presentinvention, each k^(2a) is independently an integer from about 1 to about5, preferably wherein at least one a is an integer from 1 to about 5,more preferably from 1 to about 3. Alternatively preferred, each k^(2a)is independently an integer from about 1 to about 5, preferably from 1to about 3, with from 1 to about 2 being even more preferred.

In certain other preferred embodiments of the polyesters of the presentinvention, each k^(2b) is independently an integer from about 1 to about5, preferably wherein at least one a is an integer from 1 to about 5,more preferably from 1 to about 3. Alternatively preferred, each k^(2b)is independently an integer from about 1 to about 5, preferably from 1to about 3, with from 1 to about 2 being even more preferred.

In some other preferred embodiments of the polyesters of the presentinvention, each Y^(f) is independently —OCH₂C(═O)—, —OCH(CH₃)C(═O)—,—OCH₂CH₂OCH₂C(═O)—, or —OCH₂CH₂CH₂CH₂CH₂C(═O)—, more preferably—OCH₂C(═O)— or —OCH(CH₃)C(═O)—.

In yet other preferred embodiments of the polyesters of the presentinvention, each Y^(1f) is independently —C(═O)CH₂O—, —C(═O)CH(CH₃)O—,—C(═O)CH₂OCH₂CH₂O—, or —C(═O)CH₂CH₂CH₂CH₂CH₂O—; more preferably—C(═O)CH₂O— or —C(═O)CH(CH₃)O—.

In other embodiments, the present invention is directed to compounds offormula Iva:R^(4a)—O—(Y^(1a))_(c)—O—(Y^(a))_(d)—O—R^(4a)  IVa

wherein:

-   -   each Y^(1a) is independently:        -   —C(═O)CH₂O—, —C(═O)CH(CH₃)O—, —C(═O)CH₂OCH₂CH₂O—,            —C(═O)CH₂CH₂CH₂CH₂CH₂O—, —C(═O)(CH₂)_(m)O—, or            —C(═O)CH₂O(CH₂CH₂O)_(n)—;    -   each Y^(a) is independently:        -   —OCH₂C(═O)—, —OCH(CH₃)C(═O)—, —OCH₂CH₂OCH₂C(═O)—,            —OCH₂CH₂CH₂CH₂CH₂C(═O)—, —O(CH₂)_(m)C(═O)—, or            —O(CH₂CH₂O)_(n)OCH₂C(═O)—;    -   each R^(4a) is independently H, alkyl, or aralkyl;    -   each m and n is independently an integer from about 2 to about        24; and    -   c and d are each an integer from 1 to 5, with the proviso that        the sum of c+d is an integer from about 2 to about 6.

In some preferred embodiments of compounds of formula IVa, the O betweenthe two Y groups depicted as (Y^(1a))—O—(Y^(a)) represents an etherlinkage between the Y^(1a) and Y^(a) groups such that there is only one—O— ether moiety between the two groups. By way of example, when Y^(1a)is corresponds to —C(═O)CH₂O— (glycolic ester moiety), and Y^(a)corresponds to —OCH(CH₃)C(═O)— (inverse lactic ester moiety), theresultant (Y^(1a))—O—(Y^(a)) is —COCH₂O—CH(CH₃)C(═O)—.

In other preferred embodiments of compounds of formula IVa, Y^(1a) andY^(a) are derived from different hydroxyacid or lactone precursors. Asnon-limiting examples, Y^(1a) may be —C(═O)CH₂O— (derived from glycolicacid) is and Y^(a) may be —OCH(CH₃)C(═O)— (derived from lactic acid), orY^(1a) may be derived from lactic acid and Y^(a) may be derived fromcaprolactone.

In certain preferred embodiments of compounds of formula IVa, eachY^(1a) is independently —C(═O)CH₂O—, —C(═O)CH(CH₃)O—,—C(═O)CH₂OCH₂CH₂O—, or —C(═O)CH₂CH₂CH₂CH₂CH₂O—; more preferably—C(═O)CH₂O— or —C(═O)CH(CH₃)O—

In certain other preferred embodiments of compounds of formula IVa, eachY^(a) is independently —OCH₂C(═O)—, —OCH(CH₃)C(═O)—, —OCH₂CH₂OCH₂C(═O)—,or —OCH₂CH₂CH₂CH₂CH₂C(═O)—, more preferably —OCH₂C(═O)— or—OCH(CH₃)C(═O)—.

In some preferred embodiments of compounds of formula Iva, when R^(4a)is alkyl, it is preferably C₁₋₁₂ alkyl, more preferably C₁₋₆, still morepreferably C₁₋₃, with C₁ being even more preferred. When R^(4a) isaralkyl, it is preferably phenyl-(C₁₋₆ alkyl), more preferablyphenyl-)(C₁₋₃alkyl), with benzyl being even more preferred.

The present invention also provides linear and multiarmed hydrolysablemonomeric and oligomeric linkers of formulas V, VI, VII, VIII, or IX asshown below derived from symmetrical or unsymmetrical diacids of formulaA.

wherein:

-   -   R′ and R″ are each independently a C₁₋₂₄alkylene diradical,        wherein from 1-4 of the CH₂ groups, preferably 1-3 of the CH₂        groups, within the alkyl chain are optionally independently        replaced by O or S atoms, such that each of said O or S atoms is        attached only to carbon atoms in the alkyl chain, with the        proviso that multiple heteroatoms must be separated from each        other and from the diradical chain ends by at least one carbon        atom;    -   P is a —CH₂— or —CH═CH— group;    -   each a is independently an integer from about 0 to about 6;    -   each b is independently an integer from about 1 to about 6;    -   each X is independently:        -   —OC(═O)CH₂— (inverse glycolic acid moiety), —OC(═O)CH(CH₃)—            (inverse lactic acid moiety), —OC(═O)CH₂OCH₂CH₂— (inverse            dioxanone acid moiety), —OC(═O)CH₂CH₂CH₂CH₂CH₂— (inverse            caprolactone acid moiety), —OC(═O)(CH₂)_(y)—, or            —OC(═O)CH₂(OCH₂CH₂)_(z)—; preferably —OC(═O)CH₂—,            —OC(═O)CH(CH₃)—, —OC(═O)CH₂OCH₂CH₂—, or            —OC(═O)CH₂CH₂CH₂CH₂CH₂—; more preferably —OC(═O)CH₂— or            —OC(═O)CH(CH₃)—;    -   each X¹ is independently:        -   —CH₂C(═O)O— (glycolic acid moiety), —CH(CH₃)C(═O)O— (lactic            acid moiety), —CH₂CH₂OCH₂C(═O)O— (dioxanone acid moiety),            —CH₂CH₂CH₂CH₂CH₂C(═O)O— (caprolactone acid moiety),            —(CH₂)_(y)C(═O)O—, or —(CH₂CH₂O)_(z)CH₂C(═O)O—; preferably            —CH₂C(═O)O—, —CH(CH₃)C(═O)O—, —CH₂CH₂OCH₂C(═O)O—, or            —CH₂CH₂CH₂CH₂CH₂C(═O)O—, more preferably —CH₂C(═O)O— or            —CH(CH₃)C(═O)O—;    -   each Y is independently:        -   —OCH₂C(═O)— (inverse glycolic ester moiety), —OCH(CH₃)C(═O)—            (inverse lactic ester moiety), —OCH₂CH₂OCH₂C(═O)— (inverse            dioxanone ester moiety), —OCH₂CH₂CH₂CH₂CH₂C(═O)— (inverse            caprolactone ester moiety), —O(CH₂)_(m)C(═O)—, or            —O(CH₂CH₂O)_(n)OCH₂C(═O)—; preferably —OCH₂C(═O)—,            —OCH(CH₃)C(═O)—, —OCH₂CH₂OCH₂C(═O)—, or            —OCH₂CH₂CH₂CH₂CH₂C(═O)—, more preferably —OCH₂C(═O)— or            —OCH(CH₃)C(═O)—;    -   each Y¹ is independently:        -   —C(═O)CH₂O— (glycolic ester moiety), —C(═O)CH(CH₃)O— (lactic            ester moiety), —C(═O)CH₂OCH₂CH₂O— (dioxanone ester moiety),            —C(═O)CH₂CH₂CH₂CH₂CH₂O— (caprolactone ester moiety),            —C(═O)(CH₂)_(m)O—, or —C(═O)CH₂O(CH₂CH₂O)_(n)—; preferably            —C(═O)CH₂O—, —C(═O)CH(CH₃)O—, —C(═O)CH₂OCH₂CH₂O—, or            —C(═O)CH₂CH₂CH₂CH₂CH₂O—; more preferably —C(═O)CH₂O— or            —C(═O)CH(CH₃)O—; and    -   each m, n, y, and z is independently an integer from about 2 to        about 24.

The symmetrical or unsymmetrical diacid linker of formula A of thepresent invention can be derived from the symmetrical or unsymmetricaldiacid linker precursor of formula L, wherein R′ and R″ are as hereindefined.HOOC—R″—O—R′—COOH  L

The linear and multiarmed hydrolysable monomeric and oligomeric linkersof the general formula V, VI, VII, VIII, or IX of the present inventioncan be derived from symmetrical or unsymmetrical diacid of formula A ofthe present invention according to Scheme 1 as shown below:

A few examples of structures of symmetrical or unsymmetrical diacidlinker precursor of formula L are given below.

A few examples of structures of symmetrical or unsymmetricalhydrolysable diacid linkers of formula A of the present invention aregiven below.

A few examples of structures of hydrolysable linker and crosslinkeramines derived from symmetrical or unsymmetrical ether diacids offormula A of the present invention are given below in.

-   -   wherein n is an integer from about 10 to about 50        Hydrolysable linker and crosslinker amines of formula V of the        present invention derived from symmetrical/unsymmetrical ether        diacids

A few examples of structures of hydrolysable symmetrical andunsymmetrical linker amide diols are shown below.

-   -   wherein n is an integer from about 10 to about 50, preferably        about 10 to about 30; more preferably about 10 to about 20;        still more preferably about 10 to about 12.        Hydrolysable linker amide alcohols of formula VI of the present        invention derived from symmetrical/unsymmetrical ether diacids

A few examples of structures of hydrolysable symmetrical andunsymmetrical linker and crosslinker amine acids are shown below.

Hydrolysable linker and crosslinker isocyanates of formula VII of thepresent invention derived from symmetrical/unsymmetrical ether diacids

A few examples of structures of hydrolysable linker and crosslinkeramine acids derived from symmetrical and unsymmetrical ether diacids areshown below.

Hydrolysable linker and crosslinker amine acids of formula VIII of thepresent invention derived from symmetrical/unsymmetrical ether diacids

The present invention also provides linear and multiarmed hydrolysablemonomeric and oligomeric linkers of formulas X, XI, and XII, as shownbelow derived from linear or branched precursor of formula B.

wherein:

-   -   R is a di-, tri, tetra-, penta- or hexaradical derived from        C₁₋₂₅ alkyl, aryl, or aryl-(C₁₋₆alkyl)₁₋₃-, wherein from 1-4 of        the CH₂ groups, preferably from 1-3 of the CH₂ groups, within        the alkyl chain are optionally independently replaced by O or S        atoms, preferably by O atoms, such that each of said O or S        atoms is attached only to carbon atoms in the alkyl chain, with        the proviso that the O or S atoms are separated from the di-,        tri, tetra-, penta- or hexaradical chain ends by at least one        carbon atom and that multiple O or S atoms in the di-, tri,        tetra-, penta- or hexaradical chain must be separated from each        other by at least two carbon atoms;    -   Q is a halogen (e.g., F, Cl, Br and I);    -   each a and b is independently an integer from about 1 to about        6;    -   each X is independently:        -   —OC(═O)CH₂— (inverse glycolic acid moiety), —OC(═O)CH(CH₃)—            (inverse lactic acid moiety), —OC(═O)CH₂OCH₂CH₂— (inverse            dioxanone acid moiety), —OC(═O)CH₂CH₂CH₂CH₂CH₂— (inverse            caprolactone acid moiety), —OC(═O)(CH₂)_(y)—, or            —OC(═O)CH₂(OCH₂CH₂)_(z)—; preferably —OC(═O)CH₂—,            —OC(═O)CH(CH₃)—, —OC(═O)CH₂OCH₂CH₂—, or            —OC(═O)CH₂CH₂CH₂CH₂CH₂—; more preferably —OC(═O)CH₂— or            —OC(═O)CH(CH₃)—;    -   each X¹ is independently:        -   —CH₂C(═O)O— (glycolic acid moiety), —CH(CH₃)C(═O)O— (lactic            acid moiety), —CH₂CH₂OCH₂C(═O)O— (dioxanone acid moiety),            —CH₂CH₂CH₂CH₂CH₂C(═O)O— (caprolactone acid moiety),            —(CH₂)_(y)C(═O)O—, or —(CH₂CH₂O)_(z)CH₂C(═O)O—; preferably            —CH₂C(═O)O—, —CH(CH₃)C(═O)O—, —CH₂CH₂OCH₂C(═O)O—, or            —CH₂CH₂CH₂CH₂CH₂C(═O)O—, more preferably —CH₂C(═O)O— or            —CH(CH₃)C(═O)O—;    -   each Y is independently:        -   —OCH₂C(═O)— (inverse glycolic ester moiety), —OCH(CH₃)C(═O)—            (inverse lactic ester moiety), —OCH₂CH₂OCH₂C(═O)— (inverse            dioxanone ester moiety), —OCH₂CH₂CH₂CH₂CH₂C(═O)— (inverse            caprolactone ester moiety), —O(CH₂)_(m)C(═O)—, or            —O(CH₂CH₂O)_(n)OCH₂C(═O)—; preferably —OCH₂C(═O)—,            —OCH(CH₃)C(═O)—, —OCH₂CH₂OCH₂C(═O)—, or            —OCH₂CH₂CH₂CH₂CH₂C(═O)—, more preferably —OCH₂C(═O)— or            —OCH(CH₃)C(═O)—;    -   each Y¹ is independently:        -   —C(═O)CH₂O— (glycolic ester moiety), —C(═O)CH(CH₃)O— (lactic            ester moiety), —C(═O)CH₂OCH₂CH₂O— (dioxanone ester moiety),            —C(═O)CH₂CH₂CH₂CH₂CH₂O— (caprolactone ester moiety),            —C(═O)(CH₂)_(m)O—, or —C(═O)CH₂O(CH₂CH₂O)_(n)—; preferably            —C(═O)CH₂O—, —C(═O)CH(CH₃)O—, —C(═O)CH₂OCH₂CH₂O—, or            —C(═O)CH₂CH₂CH₂CH₂CH₂O—; more preferably —C(═O)CH₂O— or            —C(═O)CH(CH₃)O—; and    -   each m, n, y, and z is independently an integer from about 2 to        about 24.

The linear or branched precursor of formula B of the present inventionis derived from diol of formula M, wherein R is as defined herein.HO—R—OH  M

The linear and multiarmed hydrolysable monomeric and oligomeric linkersof the general formula X, XI, or XII of the present invention arederived from symmetrical or unsymmetrical diols of formula B of thepresent invention as shown below in Scheme 2, wherein Q, X¹, X, Y, Y¹,a, b, and R are as previously defined.

A few examples of structures of hydrolysable linkers of formula B of thepresent invention are given below.

Hydrolysable linkers of formula B of the present invention where Q is ahalogen atom such as F, Cl, Br or I.

A few examples of structures of linear or branched hydrolysable linkerand crosslinker amines of formula X of the present invention derivedfrom p-amino benzoic acid are shown below.

Hydrolysable linker and crosslinker amines of formula X of the presentinvention derived from symmetrical/unsymmetrical ether diacids

A few examples of structures of hydrolysable linker and crosslinkeramide alcohols of formula XI of the present invention are shown below.

Hydrolysable linker and crosslinker amide alcohols of formula XI of thepresent invention

A few examples of structures of hydrolysable linker and crosslinkeramine acids of formula XII of the present invention are shown below.

Hydrolysable linker and crosslinker amine acids of formula XII of thepresent invention derived from symmetrical/unsymmetrical ether diacids

The present invention also provides novel linear and multiarmedhydrolysable monomeric and oligomeric linkers of formulas XIII-XVI asshown below derived from linear or branched diacid of formula C.

wherein:

-   -   R is a di-, tri, tetra-, penta- or hexaradical derived from        C₁₋₂₅ alkyl, aryl, or aryl-(C₁₋₆alkyl)₁₋₃-, wherein from 1-4 of        the CH₂ groups, preferably from 1-3 of the CH₂ groups, within        the alkyl chain are optionally independently replaced by O or S        atoms, preferably by O atoms, such that each of said O or S        atoms is attached only to carbon atoms in the alkyl chain, with        the proviso that the O or S atoms are separated from the di-,        tri, tetra-, penta- or hexaradical chain ends by at least one        carbon atom and that multiple O or S atoms in the di-, tri,        tetra-, penta- or hexaradical chain must be separated from each        other by at least two carbon atoms    -   each a is independently an integer from about 0 to about 6;    -   each b is independently an integer from about 1 to about 6;    -   each X is independently:        -   —OC(═O)CH₂— (inverse glycolic acid moiety), —OC(═O)CH(CH₃)—            (inverse lactic acid moiety), —OC(═O)CH₂OCH₂CH₂— (inverse            dioxanone acid moiety), —OC(═O)CH₂CH₂CH₂CH₂CH₂— (inverse            caprolactone acid moiety), —OC(═O)(CH₂)_(y)—, or            —OC(═O)CH₂(OCH₂CH₂)_(z)—; preferably —OC(═O)CH₂—,            —OC(═O)CH(CH₃)—, —OC(═O)CH₂OCH₂CH₂—, or            —OC(═O)CH₂CH₂CH₂CH₂CH₂—; more preferably —OC(═O)CH₂— or            —OC(═O)CH(CH₃)—;    -   each X¹ is independently:        -   —CH₂C(═O)O— (glycolic acid moiety), —CH(CH₃)C(═O)O— (lactic            acid moiety), —CH₂CH₂OCH₂C(═O)O— (dioxanone acid moiety),            —CH₂CH₂CH₂CH₂CH₂C(═O)O— (caprolactone acid moiety),            —(CH₂)_(y)C(═O)O—, or —(CH₂CH₂O)_(z)CH₂C(═O)O—; preferably            —CH₂C(═O)O—, —CH(CH₃)C(═O)O—, —CH₂CH₂OCH₂C(═O)O—, or            —CH₂CH₂CH₂CH₂CH₂C(═O)O—, more preferably —CH₂C(═O)O— or            —CH(CH₃)C(═O)O—;    -   each Y is independently:        -   —OCH₂C(═O)— (inverse glycolic ester moiety), —OCH(CH₃)C(═O)—            (inverse lactic ester moiety), —OCH₂CH₂OCH₂C(═O)— (inverse            dioxanone ester moiety), —OCH₂CH₂CH₂CH₂CH₂C(═O)— (inverse            caprolactone ester moiety), —O(CH₂)_(m)C(═O)—, or            —O(CH₂CH₂O)_(n)OCH₂C(═O)—; preferably —OCH₂C(═O)—,            —OCH(CH₃)C(═O)—, —OCH₂CH₂OCH₂C(═O)—, or            —OCH₂CH₂CH₂CH₂CH₂C(═O)—, more preferably —OCH₂C(═O)— or            —OCH(CH₃)C(═O)—;    -   each Y¹ is independently:        -   —C(═O)CH₂O— (glycolic ester moiety), —C(═O)CH(CH₃)O— (lactic            ester moiety), —C(═O)CH₂OCH₂CH₂O— (dioxanone ester moiety),            —C(═O)CH₂CH₂CH₂CH₂CH₂O— (caprolactone ester moiety),            —C(═O)(CH₂)_(m)O—, or —C(═O)CH₂O(CH₂CH₂O)_(n)—; preferably            —C(═O)CH₂O—, —C(═O)CH(CH₃)O—, —C(═O)CH₂OCH₂CH₂O—, or            —C(═O)CH₂CH₂CH₂CH₂CH₂O—; more preferably —C(═O)CH₂O— or            —C(═O)CH(CH₃)O—.

The linear or branched diacid of formula C of the present invention isderived from diacid of formula N, wherein R is as defined herein.HOOC—R—COOH  N

The linear and multiarmed hydrolysable monomeric and oligomeric linkersof the general formula XII, XIV, XV, and XVI of the present inventionare derived from symmetrical or unsymmetrical diacid of formula C of thepresent invention as shown below in Scheme 3.

A few examples of structures of hydrolysable linker and crosslinkersrepresenting structures XIII, XIV, XV, and XVI are shown below.

Hydrolysable Linker and Crosslinkers Representing Formula XIII, XIV, XV,and XVI

In certain cases the biodegradable region may contain at least one amidefunctionality. The cross-linker of the present cross-linker may alsoinclude an ethylene glycol oligomer, oligo(ethylene glycol),poly(ethylene oxide), poly(vinylpyrollidone), poly(propylene oxide),poly(ethyloxazoline), or combinations of these substances.

In yet another embodiment of the present invention, linear andmultiarmed hydrolysable linker amines of the present invention havegeneral structures as shown below derived from p-dioxanone andp-aminobenzoic acid:

In another embodiment of the present invention, linear and multiarmedhydrolysable linker isocyanates of the present invention have generalstructures as shown below derived from p-dioxanone and p-aminobenzoicacid:

The linkers of the present invention are typically easily incorporatedin many different polymer-processing options such as polymer microparticles, nanoparticles and slab gels. Incorporation of hydrolysablelinks and cross-links into the backbone of polymer structure shouldpermit control of overall degradation as well as the release rate ofentrapped substances.

The present invention also contemplates the application of thehydrolysable carboxylic acids, amines, amide alcohols and isocyanateslinkers and crosslinkers for preparing novel absorbable polymers withcontrolled degradation profile for biomedical applications.

The hydrolysable linkers and cross-linkers of the present invention canbe polymerized via conventional polymerization process using diol,triols, dicarboxylic acids, tricarboxylic acids, diamines, or triaminesbased on the starting difunctionalized or trifunctionalized ortetrafunctionalized molecules, including those processes that synthesizepolymers traditionally considered hydrolytically stable andnon-biodegradable.

The present invention encompasses a variety of different polymers, someof which are copolymers. The polymers of the present invention include(a) polyesters (b) polyurethanes (c) polyamides (d) polyureas anddegradable epoxy amine resin. The absorption profile of the polymers ofthe present invention will depend upon a number of factors, includingthe functionalization species used and the number of functionalizationspecies present on the functionalized phenolic (e.g., 1-6). Glycolicacid based polymers should hydrolyze faster than dioxanone based, whereas lactic acid and caprolactone based polymers should take much longerto hydrolyze than glycolic acid and dioxanone based polymers. Thedesired time range may be obtained by altering the number and type offunctionalization species as well as the number of differentfunctionalized phenolic compounds (e.g., a blend of two or morefunctionalized phenolics). The desired time range will also be impactedby moieties used for co-polymerization (e.g., difunctional compounds orlactone monomers).

The rate of hydrolysis of the materials of the present invention willdepend upon a number of factors, including the functionalization usedand the number of functionalizations present on the at leastdifunctionalized aromatic (e.g., from about 1 to about 6). For example,glycolic acid modified aromatics should generally hydrolyze more quicklythan aromatics modified with dioxanone, whereas lactic acid andcaprolactone modified aromatics should generally hydrolyze over a longerperiod of time as compared to glycolic acid and dioxanone modifiedaromatics. Furthermore, it is expected that the rate of hydrolysis willincrease as the number of functional groups is increased. Thus, desiredtime ranges for hydrolysis may be obtained by altering the number andtype of functionalization used to functionalize the aromatics.

The polymers of the present invention can be used in various medicalapplications described herein or can be further polymerized with lactonemonomers, such as glycolide, lactide, ε-caprolactone, trimethylenecarbonate, and p-dioxanone, and the resulting absorbable functionalizedphenolic/lactone copolymers can be used in the various medicalapplications described herein.

The polymers of the present invention with at least two reactive sitescan be polymerized with difunctional molecules (e.g., dicarboxylicacids, dialcohols, diisocyanates, amino-alcohols, hydroxy-carboxylicacids, and diamines) to form absorbable polymers, including but notlimited to polyesters, polyester amides, polyurethanes, polyamides,polyureas, epoxy amine resins and polyanhydrides by simplepolycondensation reactions. These polymers can be used in variousmedical applications or can be further polymerized with lactonemonomers, such as glycolide, lactide, ε-caprolactone, trimethylenecarbonate, and p-dioxanone, and the resulting absorbable polymerspotential have the medical applications described above.

In another example of the present invention, functionalized dihalogenlinkers of the present invention can be used in the preparation ofpolyesters by reacting with dicarboxylic acid compounds. Dicarboxylicacid compounds useful in the present invention have the followingstructure:HOOC—R—COOH

wherein:

-   -   R is a diradical derived from a saturated or unsaturated,        substituted or unsubstituted alkyl having from about 1 to about        18 carbon atoms, substituted or unsubstituted aryl having from        about 6 to about 18 carbon atoms, or substituted or        unsubstituted alkylaryl group having from about 7 to about 18        carbon atoms, wherein one or more, preferably from one to about        three CH₂ groups within the alkyl chain are optionally        independently replaced by O or S atoms, preferably O atoms, such        that each of said O or S atoms is attached only to carbon atoms        in the alkyl chain, with the proviso that the O or S atoms are        separated from the diradical chain ends by at least one carbon        atom and that multiple O or S atoms in the diradical chain must        be separated from each other by at least two carbon atoms.

In another example of the present invention, functionalized dicarboxylicacid linker compounds of the present invention can be used in thepreparation of polyesters by reacting with dialcohol (i.e., diol)compounds. Dialcohol compounds useful in the present invention have thefollowing structure:HO—R—OH

wherein:

-   -   R is a diradical derived from a saturated or unsaturated,        substituted or unsubstituted alkyl having from about 1 to about        18 carbon atoms, substituted or unsubstituted aryl having from        about 6 to about 18 carbon atoms, or substituted or        unsubstituted alkylaryl group having from about 7 to about 18        carbon atoms, wherein one or more, preferably from one to about        three CH₂ groups within the alkyl chain are optionally        independently replaced by O or S atoms, such that each of said O        or S atoms is attached only to carbon atoms in the alkyl chain,        with the proviso that the O or S atoms are separated from the        diradical chain ends by at least one carbon atom and that        multiple O or S atoms in the diradical chain must be separated        from each other by at least two carbon atoms.

Alternatively, polyalkylene oxides have weight average molecular weightsfrom about 500-5,000 can be used as a diol (i.e., a polydiol). Suitablediols or polydiols for use in the present invention are diol or diolrepeating units with up to 8 carbon atoms.

Examples of suitable diols include 1,2-ethanediol (ethylene glycol);1,2-propanediol (propylene glycol); 1,3-propanediol; 1,4-butanediol;1,5-pentanediol; 1,3-cyclopentanediol; 1,6-hexanediol;1,4-cyclohexanediol; 1,8-octanediol; and, combinations thereof. Examplesof polydiols include polyethylene glycol and polypropylene glycol withweight average molecular weights of 500-5000.

In another example of the present invention, functionalized dihydroxylinker amide diol compounds of the present invention can be used in thepreparation of polyurethanes by reacting with diisocyanate compounds.Examples of diisocyanates include hexamethylene diisocyanate, lysinediisocyanate, methylene diphenyl diisocyanate (e.g., MDI), hydrogenatedMDI (e.g., methylene dicyclohexyl diisocyanate), and isophoronediisocyanate, as well as any of the isocyanates of the presentinvention.

In another example of the present invention, functionalized dicarboxylicacid linker compounds of the present invention can be used in thepreparation of polyesteramides by reacting with amino-alcohol compounds.Amino-alcohols compounds useful in the present invention have thefollowing structure:HO—R—NH₂

wherein:

-   -   R is a diradical derived from a saturated or unsaturated,        substituted or unsubstituted alkyl having from about 1 to about        18 carbon atoms, substituted or unsubstituted aryl having from        about 6 to about 18 carbon atoms, or substituted or        unsubstituted alkylaryl group having from about 7 to about 18        carbon atoms, wherein one or more, preferably from one to about        three CH₂ groups within the alkyl chain are optionally        independently replaced by O or S atoms, such that each of said O        or S atoms is attached only to carbon atoms in the alkyl chain,        with the proviso that the O or S atoms are separated from the        diradical chain ends by at least one carbon atom and that        multiple O or S atoms in the diradical chain must be separated        from each other by at least two carbon atoms.

In another example of the present invention, functionalized dicarboxylicacid linker compounds of the present invention can be used in thepreparation of polyamides by reacting with diamine compounds. Diaminecompounds useful in the present invention have the following structure:H₂N—R—NH₂

wherein:

-   -   R is a diradical derived from a saturated or unsaturated,        substituted or unsubstituted alkyl having from about 1 to about        18 carbon atoms, substituted or unsubstituted aryl having from        about 6 to about 18 carbon atoms, or substituted or        unsubstituted alkylaryl group having from about 7 to about 18        carbon atoms, wherein one or more, preferably from about one to        about four, more preferably from one to about three CH₂ groups        within the alkyl chain are optionally independently replaced by        O or S atoms, such that each of said O or S atoms is attached        only to carbon atoms in the alkyl chain, with the proviso that        the O or S atoms are separated from the diradical chain ends by        at least one carbon atom and that multiple O or S atoms in the        diradical chain must be separated from each other by at least        two carbon atoms.

Linker and crosslinker amines of the present invention can also bereacted with epoxides to form degradable epoxyamine resins. The examplesof the epoxides that can be used in the present invention include butnot limited to diglycidyl ether, polyethyethyleneglucol polyglycidylether and epoxides prepared from naturally occurring fatty acids,glycidyl methacrylate and glycidyl acrylate.

In another example of the present invention, functionalized dicarboxylicacid compounds of the present invention can be used in the preparationof polyanhydrides by reacting with the dicarboxylic acid compoundsdescribed above.

The functionalized linker compounds of the present invention having morethan two reactive groups (e.g., 3) are expected to be useful in thepreparation of cross linked hydrogels and are prepared

Examples of polymers of the present invention have weight-averagemolecular weights above about 20,000 daltons or above about 100,000daltons, calculated from gel permeation chromatography (GPC) relative topolystyrene standards in tetrahydrofuran (THF) without furthercorrection.

The polymers of the present invention should be able to be processed byknown methods commonly employed in the field of synthetic polymers toprovide a variety of useful articles with valuable physical and chemicalproperties. The useful articles can be shaped by conventionalpolymer-forming techniques such as extrusion, compression molding,injection molding, solvent casting, and wet spinning. Shaped articlesprepared from the polymers are expected to be useful as degradabledevices for medical implant applications.

The present invention also relates to a composition, comprising: atleast two (e.g., 2, 3, 4, or 5) functional phenolic compounds of thepresent invention.

The present invention also relates to a composition, comprising: atleast two functionalized linker compounds, wherein the composition issuitable for use as at least one of the following: (a) a solvent fordrugs; (b) a nutritional compound; (c) a cosmetic: and, (d) apharmaceutical. Each of the compositions may further comprise anadditional component suitable for such composition. For example, whenthe composition is suitable for use as a cosmetic it may furthercomprise: one or more cosmetic ingredients. Also, when the compositionis suitable for use as a pharmaceutical it may further comprise: one ormore pharmaceutically acceptable excipients. In addition, each of thecompositions may comprise a functionalized phenolic derived from aphenolic having a property useful to that type of composition. Forexample, the starting phenolic may be (a) a nutritional supplement or afood intermediary; (b) an anticancer agent; (c) an antimicrobial agent;(d) an anti-inflammatory agent; (e) a pain-reducer; and, (f) anantioxidant agent. Also, the compositions may further comprise one ofagents (a)-(f).

The compositions of the present invention may be suitable foradministration via a route selected from oral, enteral, parenteral,topical, transdermal, ocular, vitreal, rectal, nasal, pulmonary, andvaginal.

The implantable medical devices of the present invention, comprise: atleast one absorbable polymer of the present invention. For example, apolymer of the present invention can be combined with a quantity of abiologically or pharmaceutically active compound sufficient to betherapeutically effective as a site-specific or systemic drug deliverysystem (see Gutowska et al., J. Biomater. Res., 29, 811-21 (1995) andHoffman, J. Controlled Release, 6, 297-305 (1987)). Another example ofthe present invention is a method for site-specific or systemic drugdelivery by implanting in the body of a patient in need thereof animplantable drug delivery device comprising a therapeutically effectiveamount of a biologically or a physiologically active compound incombination with at least one absorbable polymer of the presentinvention.

In another example, at least one polymer of the present invention isformed into a porous device (see Mikos et al., Biomaterials, 14, 323-329(1993) or Schugens et al., J. Biomed. Mater. Res., 30, 449-462 (1996))to allow for the attachment and growth of cells (see Bulletin of theMaterial Research Society, Special Issue on Tissue Engineering (GuestEditor: Joachim Kohn), 21(11), 22-26 (1996)). Thus, the presentinvention provides a tissue scaffold comprising a porous structure forthe attachment and proliferation of cells either in vitro or in vivoformed from at least one absorbable polymer of the present invention

The present invention also relates to an article (e.g., an implantablemedical device), comprising: a metal or polymeric substrate havingthereon a coating, wherein the coating, comprises: at least one polymerof the present invention.

The present invention also relates to a molded article prepared from atleast one polymer of the present invention.

The present invention also relates to a controlled drug delivery system,comprising: at least one polymer of the present invention physicallyadmixed with a biologically or pharmacologically active agent. Forexample, the controlled drug delivery system may comprise: abiologically or pharmacologically active agent coated with at least onepolymer of the present invention.

The present invention also relates to a controlled drug delivery system,comprising: a biologically or pharmacologically active agent physicallyembedded or dispersed into a polymeric matrix formed from at least onepolymer of the present invention.

The present invention also relates to a tissue scaffold having a porousstructure for the attachment and proliferation of cells, either in vitroor in vivo, formed from one least one polymer of the present invention.

The present invention also relates to a composition, comprising: atleast one polymer of the present invention, which has been furtherpolymerized with at least one lactone monomer selected from: glycolide,lactide, p-dioxanone, trimethylene carbonate, and caprolactone.

The present invention also relates to an implantable biomedical device,comprising: at least one polymer that has been further polymerized withat least one lactone monomer.

The present invention also relates to a biodegradable chewing gumcomposition, comprising: an effective amount of at least one polymerthat has been further polymerized with at least on lactone monomer.

The present invention also relates to an article (e.g., an implantablemedical device), comprising: a metal or polymeric substrate and havingthereon a coating, wherein said coating comprises at least one polymerthat has been further polymerized with at least one lactone monomer.

The present invention also relates to a molded article prepared from atleast one polymer that has been further polymerized with at least onelactone monomer.

The present invention also relates to a monofilament or multifilamentprepared from at least one polymer that has been further polymerizedwith at least one lactone monomer.

The present invention also relates to a controlled drug delivery system,comprising: at least one polymer that has been further polymerized withat least one lactone monomer, which has been physically admixed with abiologically or pharmacologically active agent.

The present invention also relates to a controlled drug delivery system,comprising: a biologically or pharmacologically active agent physicallyembedded or dispersed into a polymeric matrix formed from at least onepolymer that has been further polymerized with at least one lactonemonomer.

The present invention also relates to a tissue scaffold having a porousstructure for the attachment and proliferation of cells, either in vitroor in vivo, formed from at least one polymer that has been furtherpolymerized with at least one lactone monomer.

The present invention also relates to low molecular weight polymers oroligomers of the functionalized phenolic compounds of the presentinvention that are further reacted to form reactive end groups (e.g.,isocyanates, epoxides, and acrylates). Low-molecular weight polymers oroligomers as used herein means a polymer having a number averagemolecular weight of about 500-20,000 or 500-10,000. For example, some ofthe functionalized phenolic compounds behave chemically like diols. Theycan be reacted with dicarboxylic acids to form polyesters, which areusually hydroxyterminated. These hydroxyterminated oligomers can befurther reacted to form isocyanates, epoxides and acrylates. Similarlythe functionalized phenolic compounds can be reacted with isocyanates tomake urethanes. Thus, the present invention also includes a composition,comprising: at least one polymer of the present invention, which hasbeen further reacted to form reactive end groups.

The present invention also relates to polymers made from functionalizedlinker and cross-linker compounds that have been sterilized by cobalt-60radiation, electron beam radiation, and/or ethylene oxide.

“Bioabsorbable” or “absorbable” as used herein means that the materialreadily reacts or enzymatically degrades upon exposure to bodily tissuefor a relatively short period of time, thereby experiencing asignificant weight loss in that short period of time. Completebioabsorption/absorption should take place within twelve months,although it may be complete within nine months or within six months. Inthis manner, the polymers of the present invention can be fabricatedinto medical and surgical devices, which are useful for a vast array ofapplications requiring complete absorption within a relatively shorttime period.

The biological properties of the bioabsorbable polymers of the presentinvention used to form a device or part thereof, as measured by itsabsorption rate and its breaking strength retention in vivo (BSR), canbe varied to suit the needs of the particular application for which thefabricated medical device or component is intended. This can beconveniently accomplished by varying the ratio of components of thepolymer chosen.

“Pharmaceutically acceptable salts” refer to derivatives of thedisclosed compounds wherein the parent compound is modified by makingacid or base salts thereof. Examples of pharmaceutically acceptablesalts include, but are not limited to, mineral or organic acid salts ofbasic residues such as amines; alkali or organic salts of acidicresidues such as carboxylic acids; and the like. The pharmaceuticallyacceptable salts include the conventional non-toxic salts or thequaternary ammonium salts of the parent compound formed, for example,from non-toxic inorganic or organic acids. For example, suchconventional non-toxic salts include, but are not limited to, thosederived from inorganic and organic acids selected from1,2-ethanedisulfonic, 2-acetoxybenzoic, 2-hydroxyethanesulfonic, acetic,ascorbic, benzenesulfonic, benzoic, bicarbonic, carbonic, citric,edetic, ethane disulfonic, ethane sulfonic, fumaric, glucoheptonic,gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic,hydrabamic, hydrobromic, hydrochloric, hydroiodide, hydroxymaleic,hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic,maleic, malic, mandelic, methanesulfonic, napsylic, nitric, oxalic,pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic,propionic, salicyclic, stearic, subacetic, succinic, sulfamic,sulfanilic, sulfuric, tannic, tartaric, and toluenesulfonic.

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound that contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, non-aqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, Pa.,1990, p 1445, the disclosure of which is hereby incorporated byreference.

“Therapeutically effective amount” includes an amount of a compound ofthe present invention that is effective when administered alone or incombination to treat the desired indication.

“Alkyl” includes both branched and straight-chain saturated aliphatichydrocarbon groups having the specified number of carbon atoms. C₁₋₆alkyl, for example, includes C₁, C₂, C₃, C₄, C₅, and C₆ alkyl groups.Examples of alkyl include methyl, ethyl, n-propyl, i-propyl, n-butyl,s-butyl, t-butyl, n-pentyl, s-pentyl, and n-hexyl.

“Aryl” refers to an optionally substituted, mono-, di-, tri-, or othermulticyclic aromatic ring system having from about 5 to about 50 carbonatoms (and all combinations and subcombinations of ranges and specificnumbers of carbon atoms therein), with from about 6 to about 10 carbonsbeing preferred. Non-limiting examples include, for example, phenyl,naphthyl, anthracenyl, and phenanthrenyl.

Polymers of the present invention may be made in the form of randomcopolymers or block copolymers. A coupling agent may also be added tothe polymers of the present invention. A coupling agent is a reagentthat has a least two functional groups that are capable of covalentlybonding to two different monomers. Examples of coupling agents includetrifunctional or tetrafunctional polyols, oxycarboxylic acids, andpolybasic carboxylic acids (or acid anhydrides thereof). Other couplingagents include the difunctional groups (e.g., diols, diacids, diamines,and hydroxy-acids) previously discussed. The addition of the couplingagents causes the branching of long chains, which can impart desirableproperties in the molten state to the pre-polymer. Examples ofpolyfunctional coupling agents include trimethylol propane, glycerin,pentaerythritol, malic acid, citric acid, tartaric acid, trimesic acid,propane tricarboxylic acid, cyclopentane tetracarboxylic anhydride, andcombinations thereof.

A “pre-polymer” is a low-molecular weight polymer, as previouslydefined, that have reactive endgroups (e.g., hydroxy groups) that can befurther reactive with, for example, the lactone monomers.

The amount of coupling agent to be added before gelation occurs is afunction of the type of coupling agent used and the polymerizationconditions of the polymer or molecular weight of the pre-polymer towhich it is added. Generally in the range of from about 0.1 to about 10mole percent of a trifunctional or a tetrafunctional coupling agent maybe added based on the moles of polymers present or anticipated from thesynthesis.

The polymerization of a polyester of the present invention can beperformed under melt polycondensation conditions in the presence of anorganometallic catalyst at elevated temperatures. The organometalliccatalyst can be a tin-based catalyst (e.g., stannous octanoate ordibutyl tin oxide). The catalyst can be present in the mixture at a moleratio of diol, dicarboxylic acid, and optionally lactone monomer tocatalyst will be in the range of from about 15,000/1 to 80,000/1. Thereaction can be performed at a temperature not less than about 120° C.under reduced pressure. Higher polymerization temperatures may lead tofurther increases in the molecular weight of the copolymer, which may bedesirable for numerous applications. The exact reaction conditionschosen will depend on numerous factors, including the properties of thepolymer desired, the viscosity of the reaction mixture, and the glasstransition temperature and softening temperature of the polymer. Desiredreaction conditions of temperature, time and pressure can be readilydetermined by assessing these and other factors. Generally, the reactionmixture will be maintained at about 220° C. The polymerization reactioncan be allowed to proceed at this temperature until the desiredmolecular weight and percent conversion is achieved for the copolymer,which will typically take about 15 minutes to 24 hours. Increasing thereaction temperature generally decreases the reaction time needed toachieve a particular molecular weight.

Polymerization conditions for the preparation of polyesters fromdihalogen compounds with dicarboxylic acids are described in theliterature. Polymerization conditions for the preparation of other typesof polymers of the present invention (e.g., polyamides andpolyurethanes) are described in the literature. Those skilled in the artwill recognize that the polymers described herein can be made from knownprocedures.

Copolymers of the absorbable polymers of the present invention can beprepared by preparing a pre-polymer under melt polycondensationconditions, then adding at least one lactone monomer or lactonepre-polymer. The mixture could then be subjected to the desiredconditions of temperature and time to copolymerize the pre-polymer withthe lactone monomers.

A lactone pre-polymer is a pre-polymer formed by ring openingpolymerization with a known initiator (e.g., ethylene glycol, diethyleneglycol, glycerol, or other diols or triols).

The molecular weight of the pre-polymer as well as its composition canbe varied depending on the desired characteristic, which the pre-polymeris to impart to the copolymer. For example, the pre-polymers of thepresent invention, from which the copolymer is prepared, generally havea molecular weight that provides an inherent viscosity between about 0.2to about 2.0 deciliters per gram (dl/g) as measured in a 0.1 g/dlsolution of hexafluoroisopropanol at 25° C. Those skilled in the artwill recognize that the pre-polymers described herein can also be madefrom mixtures of more than one diol or dicarboxylic acid.

One of the beneficial properties of the polyesters of the presentinvention is that the ester linkages are hydrolytically unstable, andtherefore the polymer is bioabsorbable because it readily breaks downinto small segments when exposed to moist bodily tissue. In this regard,while it is envisioned that co-reactants could be incorporated into thereaction mixture of the dicarboxylic acid and the diol for the formationof the polyester pre-polymer, it is preferable that the reaction mixturedoes not contain a concentration of any co-reactant which would renderthe subsequently prepared polymer nonabsorbable. The reaction mixturecan be substantially free of any such co-reactants if the presencethereof results in a nonabsorbable polymer.

The polymers of the present invention can be melt processed by numerousmethods to prepare a vast array of useful devices. These polymers can beinjection or compression molded to make implantable medical and surgicaldevices, especially wound closure devices.

Alternatively, the polymers can be extruded to prepare fibers. Thefilaments thus produced may be fabricated into sutures or ligatures,attached to surgical needles, packaged, and sterilized by knowntechniques. The polymers of the present invention may be spun asmultifilament yarn and woven or knitted to form sponges or gauze, (ornon-woven sheets may be prepared) or used in conjunction with othermolded compressive structures as prosthetic devices within the body of ahuman or animal where it is desirable that the structure have hightensile strength and desirable levels of compliance and/or ductility.Examples include tubes, including branched tubes, for artery, vein, orintestinal repair, nerve splicing, tendon splicing, sheets for typing upand supporting damaged surface abrasions, particularly major abrasions,or areas where the skin and underlying tissues are damaged or surgicallyremoved.

Additionally, the polymers can be molded to form films which, whensterilized, are useful as adhesion prevention barriers. Anotheralternative processing technique for the polymers of the presentinvention includes solvent casting, particularly for those applicationswhere a drug delivery matrix is desired.

The polymers of the present invention can be used to coat a surface of asurgical article to enhance the lubricity of the coated surface. Thepolymer may be applied as a coating using conventional techniques. Forexample, the polymer may be solubilized in a dilute solution of avolatile organic solvent (e.g. acetone, methanol, ethyl acetate, ortoluene), and then the article can be immersed in the solution to coatits surface. Once the surface is coated, the surgical article can beremoved from the solution where it can be dried at an elevatedtemperature until the solvent and any residual reactants are removed.

For coating applications, the polymer should exhibit an inherentviscosity, as measured in a 0.1 gram per deciliter (g/dl) ofhexafluoroisopropanol (HFIP), between about 0.05-2.0 dl/g or about0.10-0.80 dl/g. If the inherent viscosity were less than about 0.05dl/g, then the polymer may not have the integrity necessary for thepreparation of films or coatings for the surfaces of various surgicaland medical articles. On the other hand, it is possible to use polymerswith an inherent viscosity greater than about 2.0 dl/g, though it may bedifficult to do so.

Although numerous surgical articles (including but not limited toendoscopic instruments) can be coated with the polymer of the presentinvention to improve the surface properties of the article, specificsurgical articles include surgical sutures, stents, and needles. Forexample the surgical article can be a suture, which can be attached to aneedle. The suture can be a synthetic absorbable suture. These suturesare derived, for example, from homopolymers and copolymers of lactonemonomers such as glycolide, lactide, ε-caprolactone, 1,4-dioxanone, andtrimethylene carbonate. The suture can be a braided multifilament suturecomposed of polyglycolide or poly(glycolide-co-lactide).

The amount of coating polymer to be applied on the surface of a braidedsuture can be readily determined empirically, and will depend on theparticular copolymer and suture chosen. Ideally, the amount of coatingcopolymer applied to the surface of the suture may range from about0.5-30 percent of the weight of the coated suture or from about 1.0-20weight percent, or from 1-5 percent by weight. If the amount of coatingon the suture were greater than about 30 weight percent, then it mayincrease the risk that the coating may flake off when the suture ispassed through tissue

Sutures coated with the polymers of the present invention are desirablebecause they have a more slippery feel, thus making it easier for thesurgeon to slide a knot down the suture to the site of surgical trauma.In addition, the suture is more pliable, and therefore is easier for thesurgeon to manipulate during use. These advantages are exhibited incomparison to sutures which do not have their surfaces coated with thepolymer of the present invention.

When the article of the present invention is a metal stent, the amountof coating applied to the surface of the article is an amount whichcreates a layer with a thickness ranging, for example, between about2-20 microns on the stent or about 4-8 microns. If the amount of coatingon the stent were such that the thickness of the coating layer wasgreater than about 20 microns, or if the thickness was less than about 2microns, then the desired performance of the stent as it is passedthrough tissue may not be achieved.

When the article of the present invention is a surgical needle, theamount of coating applied to the surface of the article is an amountwhich creates a layer with a thickness ranging, for example, betweenabout 2-20 microns on the needle or about 4-8 microns. If the amount ofcoating on the needle were such that the thickness of the coating layerwas greater than about 20 microns, or if the thickness was less thanabout 2 microns, then the desired performance of the needle as it ispassed through tissue may not be achieved.

The polymers of the present invention can also be used as apharmaceutical carrier in a drug delivery matrix. To form this matrixthe polymer can be mixed with a therapeutic agent to form the matrix.There are a variety of different therapeutic agents, which can be usedin conjunction with the polymers of the invention. In general,therapeutic agents which may be administered via the pharmaceuticalcompositions of the invention include, antiinfectives such asantibiotics and antiviral agents; analgesics and analgesic combinations;anorexics; antihelmintics; antiarthritics; antiasthmatic agents;anticonvulsants; antidepressants; antidiuretic agents; antidiarrheals;antihistamines; antiinflammatory agents; antimigraine preparations;antinauseants; antineoplastics; antiparkinsonism drugs; antipruritics;antipsychotics; antipyretics, antispasmodics; anticholinergics;sympathomimetics; xanthine derivatives; cardiovascular preparationsincluding calcium channel blockers and beta-blockers such as pindololand antiarrhythmics; antihypertensives; diuretics; vasodilatorsincluding general coronary, peripheral and cerebral; central nervoussystem stimulants; cough and cold preparations, including decongestants;hormones such as estradiol and other steroids, includingcorticosteroids; hypnotics; immunosuppressives; muscle relaxants;parasympatholytics; psychostimulants; sedatives; and tranquilizers; andnaturally derived or genetically engineered proteins, polysaccharides,glycoproteins, or lipoproteins.

The drug delivery matrix may be administered in any suitable dosage formincluding orally, parenterally, subcutaneously as an implant, vaginally,or as a suppository. Matrix formulations containing the polymers of thepresent invention may be formulated by mixing one or more therapeuticagents with the polymer. The therapeutic agent, may be present as aliquid, a finely divided solid, or any other appropriate physical form.Typically, but optionally, the matrix will include one or moreadditives, e.g., nontoxic auxiliary substances such as diluents,carriers, excipients, or stabilizers. Other suitable additives may beformulated with the polymers of the present invention andpharmaceutically active agent. If water is to be used, then it can beuseful to add it just before administration.

The amount of therapeutic agent will be dependent upon the particulardrug employed and medical condition being treated. Typically, the amountof drug represents about 0.001%-70%, 0.001%-50%, or 0.001%-20% by weightof the matrix.

The quantity and type of polymer incorporated into a composition (e.g.,parenterally delivered composition) will vary depending on the releaseprofile desired and the amount of drug employed. The product may containblends of polymers of the present invention to provide the desiredrelease profile or consistency to a given formulation.

The polymers of the present invention, upon contact with body fluidsincluding blood or the like, undergoes gradual degradation (mainlythrough hydrolysis) with concomitant release of the dispersed drug for asustained or extended period (as compared to the release from anisotonic saline solution). This can result in prolonged delivery (e.g.,over 1-2,000 hours or 2-800 hours) of effective amounts (e.g., 0.0001mg/kg/hour to 10 mg/kg/hour) of the drug. This dosage form can beadministered as is necessary depending on the subject being treated, theseverity of the affliction, and the judgment of the prescribingphysician.

Individual formulations of drugs and polymers of the present inventionmay be tested in appropriate in vitro and in vivo models to achieve thedesired drug release profiles. For example, a drug could be formulatedwith a polymer of the present invention and orally administered to ananimal. The drug release profile could then be monitored by appropriatemeans such as, by taking blood samples at specific times and assayingthe samples for drug concentration. Following this or similarprocedures, those skilled in the art will be able to formulate a varietyof formulations.

EXAMPLES

The present invention will now be illustrated by reference to thefollowing specific, non-limiting examples. Those skilled in the art oforganic synthesis may be aware of still other synthetic routes to theinvention compounds. The reagents and intermediates used herein arecommercially available or may be prepared according to standardliterature procedures.

Example 1 Synthesis of chloro-acetic acid 2-(2-chloro-acetoxy)-ethylester

A solution of ethylene glycol (100 grams, 1.611 moles), chloro aceticacid (385 grams, 4.031 moles) and para-toluenesulphonic acid (1 gram) intoluene (750 ml) in a 2 lit 4 neck round bottom flask equipped with amechanical stirrer and dean-stark apparatus was refluxed for 8 hours,cooled to room temperature. The toluene layer was washed with water(2×300 ml), 5% sodium bicarbonate solution (3×500 ml), water (2×300 ml),dried over sodium sulphate and distilled to get crude 1, which waspurified by high vacuum distillation to get pure 1 (242 grams, 69.8%),which slowly crystallized to white crystals with a melting point of 44°C. The pure product 1 was also characterized using ¹H NMR spectroscopyin CDCl₃: δ 4.16 (s, 2H, CH₂), 4.85 (s, 2H, CH₂).

Example 2

To a solution of 4-nitrobenzoic acid (155 grams, 927 mmoles), triethylamine (101.6 grams, 1.004 moles) in dimethylformamide (250 ml) was added1 (60 grams, 279 mmoles) in small portions and stirred at 50° C. for 6hours. The solids were filtered off, the dimethylformamide solution wasadded onto 5% sodium bicarbonate solution (1 lit), filtered crude 2,recrystallised in chloroform:methanol (1:1) to get pure 2 (87 grams,65.5%) as a off-white powder with a melting point of 116.5-118° C. Thepure product 2 was also characterized using ¹H NMR spectroscopy inCDCl₃: δ 4.46 (s, 2H, CH₂), 4.88 (s, 2H, CH₂), 8.30 (dd, 4H, Ar).

Example 3

The compound from Example 2 (76 grams, 159.66 mmoles) was dissolved indimethylformamide (150 ml) in a pressure vessel, Raney-Nickel (30 grams)added and the mixture stirred under an atmosphere of hydrogen (4 Kg) for24 hours. The catalyst was removed by filtration, and 3 was precipitatedby adding methanol, filtered, dried to get pure 3 (54 grams, 81.3%) as aoff-white powder with a melting point of 183-185° C. The pure product 3was also characterized using ¹H NMR spectroscopy in DMSO-d₆: δ4.32 (s,2H, CH₂), 4.78 (s, 2H, CH₂), 6.10 (s, 2H, NH₂), 6.60 (d, 2H, Ar), 7.78(d, 2H, Ar).

Hydrolysis

Example-3—0.5 grams

Aldrich pH9 buffer—50 ml

Temperature—100° C.

Hydrolyzed in 5 hours

Example 4 Chloro-acetic acid 2-(2-chloro-acetoxy)-ethyl ester

A solution ethylene glycol (100 grams, 1.611 moles), chloroacetic acid(385 grams, 4.031 moles) and para-toluenesulphonic acid (1 gram) intoluene (750 ml) in a 2 lit, 4 neck round bottom flask equipped with amechanical stirrer and a dean-stark apparatus was refluxed for 8 hoursand cooled to room temperature. The toluene layer was washed with water(2×300 ml), 5% sodium bicarbonate solution (3×500 ml), water (2×300 ml),dried over sodium sulphate and distilled to get crude 4, which waspurified by high vacuum distillation to get pure 4 (242 grams, 69.8%),which slowly crystallized to white crystals. m.p: 44° C. The pureproduct 4 was also characterized using ¹H NMR spectroscopy in CDCl₃: δ4.16 (s, 2H, CH₂), 4.85 (s, 2H, CH₂).

Example 5 (4-Nitro-phenoxy)-aceticacid-2-[2-(4-nitro-phenoxy)-acetoxy]-ethyl ester

To a mixture of 4-nitrophenol (50 grams, 359.42 mmoles), potassiumcarbonate (248 grams, 1.794 moles), sodium iodide (5 grams) in acetone(250 ml) was added 4 (25 grams, 116.25 mmoles) in small portions andstirred at reflux for 24 hours. Acetone was distilled and water (1000ml) was added. Crude 5 was filtered, dried and purified by columnchromatography on silica gel using hexane:ethyl acetate (95:5) to getpure 5 (30 grams, 61.4%) as a white powder. m.p: 138-139° C. The pureproduct 5 was also characterized using ¹H NMR spectroscopy in CDCl₃: δ4.49 (s, 2H, CH₂), 4.74 (s, 2H, CH₂), 6.98 (d, 2H, Ar), 8.24 (d, 2H,Ar).

Example 6 (4-Amino-phenoxy)-aceticacid-2-[2-(4-amino-phenoxy)-acetoxy]-ethyl ester

(4-Nitro-phenoxy)-acetic acid-2-[2-(4-nitro-phenoxy)-acetoxy]-ethylester 5 (100 grams, 238 mmoles) was dissolved in dry dimethylformamide(500 ml) in a pressure vessel, palladium on carbon (5%, 22 grams) added,and the mixture was stirred under hydrogen atmosphere (4 Kg) for 6hours. The catalyst was removed by filtration and to the filtrate wasadded ice-cold water (2.5 lit). Crude 6 was filtered off, dried andrecrystallised in a mixture of methanol:chloroform (1:1) to give pure 6(65 grams, 78%) as a light brown shining powder. m.p: 124-125.8° C. Thepure product 6 was also characterized using ¹H NMR spectroscopy inCDCl₃: δ 4.40 (s, 2H, OCOCH2), 4.50 (s, 2H, OCH₂), 6.54 (d, 2H, Ar),6.70 (d, 2H, Ar), 7.26 (s, 2H, NH₂).

Example 7 6-Bromo-hexanoic acid 2-(6-bromo-hexanoyloxy)-ethyl ester

A solution of ethylene glycol (5 grams, 80.55 mmoles), 6-bromohexanoicacid (47 grams, 240.96 mmoles) and para-toluenesulphonic acid (0.5 gram)in toluene (150 ml) in a 500 ml 4 neck round bottom flask equipped witha mechanical stirrer and dean-stark apparatus was refluxed for 4 hoursand cooled to room temperature. The toluene layer was washed with water(2×100 ml), 5% sodium bicarbonate solution (3×50 ml), water (2×100 ml),dried over sodium sulphate and distilled to get example 7 (30 grams,91%) as a light yellow syrup with a melting point of 44° C. The pureproduct 7 was also characterized using ¹H NMR spectroscopy in CDCl₃: δ1.45 (m, 2H, CH₂), 1.59 (m, 2H, CH₂), 1.82 (m, 2H, CH₂), 2.26 (t, 2H,CH₂), 3.34 (t, 2H, CH₂), 4.18 (s, 2H, CH₂).

Example 8

To a solution of 4-nitrobenzoic acid (12 grams, 71.80 mmoles),triethylamine (11 grams, 108.70 mmoles) in dimethylformamide (25 ml) wasadded 7 (10 grams, 24.02 mmoles) drop wise and stirred at roomtemperature for 16 hours. The solids were filtered off, thedimethylformamide solution was added onto 5% sodium bicarbonate solution(1 lit), crude 8 was extracted into chloroform, dried over sodiumsulphate distilled and purified by column chromatography on silica gelusing toluene as eluant to get pure 8 (9 grams, 63.8%) as a light creampowder. m.p: 71-73° C. The pure product 8 was also characterized using¹H NMR spectroscopy in CDCl₃: δ 1.50 (m, 2H, CH₂), 1.80 (m, 4H, CH₂),2.36 (t, 2H, CH₂), 4.26 (s 2H, CH₂), 4.34 (t, 2H, CH₂), 8.28 (dd, 4H,Ar).

Example 9

The compound from Example 8 (25 grams, 44.283 mmoles) was dissolved inDMF (200 ml) in a pressure vessel, Raney-Nickel (15 grams) added and themixture stirred under hydrogen atmosphere (4 Kg) for 24 hours. Thecatalyst was removed by filtration, DMF distilled under vacuum and crude9 was purified by column chromatography using chloroform: Ethyl acetate(9:1) as eluent to get pure 9 (15 grams, 67.2%) as a light brown powder.m.p: 70-73° C. The pure product 9 was also characterized using ¹H NMRspectroscopy in CDCl₃: δ 1.46 (m, 2H, CH₂), 1.70 (m, 4H, CH₂), 2.32 (t,2H, CH₂), 4.14 (bs, 2H, NH₂), 4.20 (s &t, 4H, CH₂), 6.56 (d, 2H, Ar),7.80 (d, 2H, Ar).

Hydrolysis

Example-9—0.5 grams

Aldrich pH9 buffer—50 ml

Temperature—100° C.

Hydrolyzed in 15 hours (By TLC 90% hydrolyzed)

Example 10 Chloro-acetic acid 3-(2-chloro-acetoxy)-propyl ester

A solution of 1,3-propanediol (25 grams, 328.55 mmoles), chloroaceticacid (94 grams, 984.39 mmoles) and para-toluenesulphonic acid (1 gram)in toluene (250 ml) in a 1 lit, 4 neck round bottom flask equipped witha mechanical stirrer and dean-stark apparatus was refluxed for 8 hours,cooled to room temperature. The toluene layer was washed with water(2×300 ml), 5% sodium bicarbonate solution (3×300 ml), water (2×300 ml),dried over sodium sulphate and distilled to get crude 10, which waspurified by high vacuum distillation to get example 10 (72 grams, 95.6%)as colorless liquid. The pure product 10 was also characterized using ¹HNMR spectroscopy in CDCl₃: δ 2.10 (m, 2H, CH₂), 4.08 (s, 4H, CH₂), 4.30(t, 4H, CH₂).

Example 11

To a solution of 4-nitrobenzoic acid (32.8 grams, 196.26 mmoles),triethylamine (30 grams, 296.47 mmoles) in dimethylformamide (40 ml) wasadded 10 (15 grams, 65.48 mmoles) in small portions and stirred at roomtemperature for 6 hours. The solids were filtered off, thedimethylformamide solution was added onto 5% sodium bicarbonate solution(150 ml), filtered crude 11, recrystallised in chloroform:methanol (1:1)to get pure 11 (9 grams, 28.1%) as a light cream powder. m.p: 120-121.8°C. The pure product 11 was also characterized using ¹H NMR spectroscopyin CDCl₃: δ 2.08 (m, 1H, CH), 4.30 (t, 2H, CH₂), 4.88 (s, 2H, CH₂), 8.30(dd, 4H, Ar).

Example 12

The compound from Example 11 (5 grams, 10.20 mmoles) was dissolved indimethylformamide (100 ml) and methanol (100 ml) in a pressure vessel,Raney-Nickel (3 grams) added and the mixture stirred under hydrogenatmosphere (4 Kg) for 24 hours. The catalyst was removed by filtration,solvent distilled under vacuum, added ice water (20 ml), filtered crude12 which was recrystallised from a mixture of dimethylformamide:methanol(1:7) to get pure 12 (3 grams, 68.49%) as a light brown powder. m.p:130.3-132.4° C. (Corrected to 142-144° C.). The pure product 12 was alsocharacterized using ¹H NMR spectroscopy in DMSO-d₆: δ 2.00 (m, 1H, CH₂),4.22 (t, 2H, CH2), 4.74 (s, 2H, CH₂), 5.36 (bs, 2H, NH₂), 6.60 (d, 2H,Ar), 7.74 (d, 2H, Ar).

Hydrolysis

Example-12—0.5 grams

Aldrich pH9 buffer—50 ml

Temperature—100° C.

Hydrolyzed in 29 hours (by TLC 90% hydrolyzed)

Example 13 Synthesis of chloro-acetic acid3-(2-chloro-acetoxy)-2,2-bis-(2-chloro-acetoxymethyl)-propyl ester

A solution pentaerythritol (25 grams, 183.62 mmoles), chloroacetic acid(105.2 grams, 1.10 moles) and para-toluenesulphonic acid (2 gram) intoluene (500 ml) in a 2 lit 4 neck round bottom flask equipped with amechanical stirrer and dean-stark apparatus was refluxed for 8 hours,cooled to room temperature. The toluene layer was washed with water(2×300 ml), 5% sodium bicarbonate solution (3×500 ml), water (2×300 ml),dried over sodium sulphate and distilled to get crude 13, which waspurified by recrystallization from chloroform:hexane (1:7) to get pure13 (77 grams, 94.8%), as a white powder with a melting point of 94-96°C. The pure product 13 was also characterized using ¹H NMR spectroscopyin CDCl₃: δ 4.16 (s, 2H, CH₂), 4.28 (s, 2H, CH₂).

Example 14

To a solution of 4-nitrobenzoic acid (11.3 grams, 67.61 mmoles),triethylamine (9.2 grams, 90.91 mmoles) in dimethylformamide (25 ml) wasadded chloroacetic acid3-(2-chloro-acetoxy)-2,2-bis-(2-chloro-acetoxymethyl)-propyl ester 13 (5grams, 11.31 mmoles) in small portions and stirred at room temperaturefor 5 hours. The solids were filtered off; the dimethylformamidesolution was added onto 5% sodium bicarbonate solution (1 lit),filtered, washed with methanol and dried to get 14 (9 grams, 83.6%) asan off-white powder. Analytical sample was prepared by columnchromatography on silica gel using chloroform as eluant. m.p: 117-121°C. The pure product 14 was also characterized using ¹H NMR spectroscopyin CDCl₃: δ 4.14 (s, 2H, CH₂), 4.84 (s, 2H, CH₂), 8.25 (dd, 4H, Ar)

Example 15

The compound from Example 14 (25 grams, 26.26 mmoles) was dissolved indimethylformamide (100 ml) in a pressure vessel, Raney-Nickel (10 grams)added and the mixture stirred under hydrogen atmosphere (4 Kg) for 5hours. The catalyst was removed by filtration, and 15 was precipitatedby adding methanol, filtered, dried to get pure 15 (20 grams, 91.5%) asa white fluffy powder with a melting point of 192-194.4° C. The pureproduct 15 was also characterized using ¹H NMR spectroscopy in DMSO-d₆:δ 4.25 (s, 2H, CH₂), 4.81 (s, 2H, CH₂), 6.09 (bs, 2H, NH₂), 6.55 (d, 2H,Ar), 7.67 (d, 2H, Ar).

Hydrolysis

Example-15—0.5 grams

Aldrich pH9 buffer—50 ml

Temperature—100° C.

Hydrolyzed in 6 hours

Example 16 Synthesis of chloro-acetic acid2,3-bis-(2-chloro-acetoxy)-propyl ester

A solution of glycerol (25 grams, 271.47 mmoles), chloroacetic acid (116grams, 1.214 moles) and para-toluenesulphonic acid (2 gram) in toluene(500 ml) in a 2 lit 4 neck round bottom flask equipped with a mechanicalstirrer and dean-stark apparatus was refluxed for 6 hours, cooled toroom temperature. The toluene layer was washed with water (2×300 ml), 5%sodium bicarbonate solution (3×500 ml), water (2×300 ml), dried oversodium sulphate and distilled to get crude 16 (67 grams, 76%) as acolorless liquid.

Example 17

To a solution of 4-nitrobenzoic acid (23.4 grams, 140.01 mmoles),triethyl amine (18.9 grams, 186.77 mmoles) in dimethylformamide (30 ml)was added chloroacetic acid 2,3-bis-(2-chloro-acetoxy)-propyl ester 16(10 grams, 31.09 mmoles) in small portions and stirred at roomtemperature for 16 hours. The solids were filtered off, thedimethylformamide solution was added onto 5% sodium bicarbonate solution(500 ml), extracted into chloroform washed with water (2×50 ml), driedover sodium sulphate, distilled to get crude 17, which was purified bycolumn chromatography on silica gel using toluene as eluant to get pure17 (6 grams, 27%) as a light yellow syrup. The pure product 17 was alsocharacterized using ¹H NMR spectroscopy in DMSO-d₆: δ 4.42 (m, 4H, CH₂),4.92 (overlapped s, 6H, CH₂), 5.42 (m, 1H, CH), 8.28 (overlapped d, 12H,Ar).

Example 18

The compound from Example 17 (10 grams, 14.02 mmoles) was dissolved indimethylformamide (150 ml) in a pressure vessel, Raney-Nickel (15 grams)added and the mixture stirred under hydrogen atmosphere (4 Kg) for 16hours. The catalyst was removed by filtration, filtrate poured on to icewater (300 ml), extracted with ethyl acetate dried over sodium sulphate,treated with charcoal filtered and distilled off the solvent undervacuum to get pure 18 (6 grams, 68.7%) as a light yellow syrup. The pureproduct 18 was also characterized using ¹H NMR spectroscopy in a mixtureof CDCl₃ and DMSO-d₆: δ 4.35 (m, 4H, CH₂), 4.78 (over lapped s, 6H,CH₂), 5.30 (m, 1H, CH), 6.62 (d, 2H, Ar), 7.70 (d, 2H, Ar)

Hydrolysis

Example-18—0.5 grams

Aldrich pH9 buffer—50 ml

Temperature—100° C.

Hydrolyzed in 10 hours

Example 19 Chloro-acetic acid 4-(2-chloro-acetoxy)-butyl ester

A solution 1,4-butanediol (75 grams, 832.22 mmoles), chloroacetic acid(240 grams, 2.513 moles) and para-toluenesulphonic acid (3 grams) intoluene (750 ml) in a 2 lit 4 neck round bottom flask equipped with amechanical stirrer and dean-stark apparatus was refluxed for 6 hours,cooled to room temperature. The toluene layer was washed with water(2×300 ml), 5% sodium bicarbonate solution (3×500 ml), water (2×300 ml),dried over sodium sulphate and distilled to get crude 19, which waspurified by recrystallization in chloroform:hexane (1:7) to get pure 19(92 grams, 69.8%) as a white fluffy powder. m.p: 74-76.5° C. The pureproduct 19 was also characterized using ¹H NMR spectroscopy in CDCl₃: δ1.78 (t, 2H, CH₂), 4.05 (s, 2H, CH₂), 4.25 (t, 2H, CH₂).

Example 20

To a solution of 4-nitrobenzoic acid (10.3 grams, 61.63 mmoles),triethylamine (10.4 grams, 102.77 mmoles) in dimethylformamide (25 ml)was added chloroacetic acid 4-(2-chloro-acetoxy)-butyl ester 19 (5grams, 20.56 mmoles) in small portions and stirred at room temperaturefor 16 hours. The solids were filtered off, the dimethylformamidesolution was added onto 5% sodium bicarbonate solution (250 ml),filtered, crude 25, recrystallized in chloroform:hexane (1:7) to getpure 20 (4.8 grams, 46.3%) as a white powder. m.p: 122.5-125° C. Thepure product 20 was also characterized using ¹H NMR spectroscopy inCDCl₃: δ 1.78 (t, 2H, CH₂), 4.24 (t, 2H, CH₂), 4.86 (s, 2H, CH₂) 8.32(dd, 4H, Ar).

Example 21

The compound from Example 20 (25 grams, 49.60 mmoles) was dissolved indimethylformamide (200 ml) in a pressure vessel, Raney-Nickel (15 grams)added and the mixture stirred under hydrogen atmosphere (4 Kg) for 18hours. The catalyst was removed by filtration and to the filtrate wasadded ice water (500 ml), filtered, dried and washed with hot ethylacetate to get pure 21 (14 grams, 63.5%) as a white powder. m.p:192.7-195.4. The pure product 21 was also characterized using ¹H NMRspectroscopy in (DMSO-d₆) δ 1.75 (t, 2H, CH₂), 4.17 (t, 2H, CH₂), 4.85(s, 2H, CH₂), 6.15 (s, 2H, NH2), 6.67 (d, 2H, Ar), 7.80 (d, 2H, Ar).

Hydrolysis

Example-21—0.5 grams

Aldrich pH 9 buffer—50 ml

Temperature—100° C.

Hydrolyzed in 24 hours (By TLC 95% hydrolyzed)

Example 22 Chloro-acetic acid 2-[2-(2-chloro-acetoxy)-ethoxy]-ethylester

A solution diethyleneglycol (25 grams, 231.20 mmoles), chloroacetic acid(66 grams, 691.17 mmoles) and para-toluenesulphonic acid (1 gram) intoluene (350 ml) in a 1 lit 4 neck round bottom flask equipped with amechanical stirrer and dean-stark apparatus was refluxed for 6 hours,cooled to room temperature. The toluene layer was washed with water(2×300 ml), 5% sodium bicarbonate solution (3×500 ml), water (2×300 ml),dried over sodium sulphate and distilled to get 22 (56 grams, 93.4%) aslight yellow syrup. The pure product 22 was also characterized using ¹HNMR spectroscopy in CDCl₃: δ 3.75 (t, 2H, CH₂), 4.12 (s, 2H, CH₂), 4.36(t, 2H, CH₂)

Example 23

To a solution of 4-nitro benzoic acid (29 grams, 173.52 mmoles),triethylamine (29 grams, 286.58 mmoles) in dimethylformamide (75 ml) wasadded 22 (15 grams, 57.89 mmoles) drop wise and stirred at roomtemperature for 18 hours. The solids were filtered off,dimethylformamide solution was added on to ice water (300 ml), extractedwith chloroform, washed with 5% sodium bicarbonate solution (3×50 ml),water (100 ml), dried over sodium sulphate, distilled to get crude 23which was purified by column chromatography on silica gel using benzeneas eluant to get pure 23 (10 grams, 33.22%) as light cream powder. m.p:62-64° C. The pure product 23 was also characterized using ¹H NMRspectroscopy in CDCl₃: ¹H NMR (CDCl₃) δ 3.72 (t, 2H, CH₂), 4.34 (t, 2H,CH₂), 4.92 (s, 2H, CH₂), 8.30 (overlapped d, 4H, Ar).

Example 24

The compound from Example 23 (80 grams, 173.91 mmoles) was dissolved indimethylformamide (300 ml) in a pressure vessel, Raney-Nickel (40 grams)added and the mixture stirred under an atmosphere of hydrogen (4 Kg) for16 hours. The catalyst was removed by filtration and to the filtrate wasadded ice water (700 ml), filtered, dried and washed with hot methanolto get pure 24 (56.6 grams, 80%) as a white powder. m.p: 136-137° C. Thepure product 24 was also characterized using ¹H NMR spectroscopy in amixture of CDCl₃ and DMSO-d₆: δ 3.62 (t, 2H, CH₂), 4.20 (t, 2H, CH2),4.81 (s, 2H, CH₂), 6.08 (s, 2H, NH₂), 6.58 (d, 2H, Ar), 7.78 (d, 2H,Ar).

Hydrolysis

Example-24—0.5 grams

Aldrich pH9 buffer—50 ml

Temperature—100° C.

Hydrolyzed in 3 hours

Example-25 Chlorocarbonylmethoxy-acetyl chloride

A solution of diglycolic acid (100 grams, 745.76 mmol) and thionylchloride (125 ml, 1.713 mol) was refluxed for 5 hours. Excess thionylchloride was distilled off and the acid chloride was purified by highvacuum distillation to get pure product 25 (110 grams, 86.2%) as a lightyellow liquid. bp: 84-87° C./2 mm Hg.

Example-26 (4-Nitro-phenoxycarbonylmethoxy)-acetic acid 4-nitro-phenylester

To a solution of 4-nitrophenol (81.35 grams, 584.78 mmol) and pyridine(47.3 ml, 584.82 mmol) in chloroform at 0° C. under N₂ atmosphere wasadded diglycolyl chloride 25 (50 grams, 292.43 mmol) drop wise. Furtherstirred at 0° C. for 8 hours, filtered the separated solid, anddiscarded the chloroform layer which continued unreacted 4-Nitrophenolalong with some product. The filtered solid was taken into water (2000ml), extracted with ethyl acetate (3×300 ml), the combined ethyl acetatelayer washed with 5% sodium bicarbonate (3×300 ml), water (1×300 ml),dried over sodium sulphate, distilled off 80% ethyl acetate and to theresidue added hexane (250 ml), filtered the precipitated product to getdinitro compound 26 (60 grams) as white powder. mp: 161.8-163.6° C.,Mass: M+Na=399. The pure product 26 was also characterized using ¹H NMRspectroscopy in DMSO-d₆: δ 4.64 (s, 2H, CH₂), 7.42 (d, 2H, Ar), 8.36 (d,4H, Ar).

HPLC Conditions

Column: Inertsil C-18, 250×4.6 mm 5.0 μm

Flow: 1.000 ml/min

Mobile Phase: A (20% Water): B (80% ACN)

Purity: 99.035%

Example-27 (4-Amino-phenoxycarbonylmethoxy)-acetic acid 4-amino-phenylester

(4-nitro-phenoxycarbonylmethoxy)-acetic acid 4-nitro-phenyl ester 26 (10grams, 26.59 mmoles) was dissolved in dimethylformamide (100 ml) in apressure vessel, 10% palladium carbon (3 grams, 50% wet) added and themixture stirred under an atmosphere of hydrogen (3 Kg) for 4 hours. Thecatalyst was removed by filtration, and diamine was precipitated byadding water, filtered, dried and recrystallised from ethyl acetate toget pure diamine 27 (4 grams, 47.6%) as off-white powder. m.p: 122-123°C. The pure product 27 was also characterized using ¹H NMR spectroscopyin DMSO-d₆: δ 4.47 (s, 2H, CH₂), 5.04 (s, 2H, NH₂), 6.54 (d, 2H, Ar),6.79 (d, 2H, Ar).

HPLC Conditions

Column: Inertsil C-18, 250×4.6 mm 5.0 μm

Flow: 0.600 ml/min

Mobile Phase: D (50% Water): A (50% ACN)

Purity: 99.037%

Example-28 (4-Isocyanato-phenoxycarbonylmethoxy)-acetic acid4-isocyanato-phenyl ester

To a solution of (4-amino-phenoxycarbonylmethoxy)-acetic acid4-amino-phenyl ester (27) (2 grams, 6.32 mmoles) in dry 1,4-dioxane (32ml) under nitrogen atmosphere was cooled to 10° C. and added a solutionof diphosgene (4 grams, 13.47 mmoles) in 1,4-dioxane (8 ml) in one lotand heated to a temperature of 100° C. for 2 hours. The condenser wasthen arranged for distillation and solvent removed by distillation atatmospheric pressure until the volume of the reaction mixture wasreduced to approximately one third. Fresh dry dioxane (10 ml) was addedand distilled off the solvents under vacuum. The residue wasre-evaporated two times from dry dioxane (2×10 ml) to give crude 28(4-Isocyanato-phenoxycarbonylmethoxy)-acetic acid 4-isocyanato-phenylester, which was recrystallized from toluene as a white powder with amelting point of 150.5-152.4° C., IR: 2316.1 cm⁻¹, 2274.3 cm⁻¹. The pureproduct 28 was also characterized using ¹H NMR spectroscopy in CDCl₃: δ4.56 (s, 2H, CH₂), 7.10 (s, 4H, Ar).

Example 29 Synthesis of (2-Bromo-ethoxy)-acetic acid

To 48% hydrobromic acid (372 ml) at 0° C. was added drop wiseconcentrated sulphuric acid (84.1 ml) and stirred for 10 minutes. Atthis temperature was added para dioxanone (70 grams, 685.6 mmol)followed by further stifling at room temperature for 1 hour. Thereaction mixture was then was heated at 100° C. for 2 hours 30 minutes,followed by overnight cooling at room temperature. The reaction mixturewas taken in to ice water, extracted with ethyl acetate (4×250 ml),dried over sodium sulphate, distilled to get crude acid 29 (98 grams)with a GC purity of 78.1%, which was fractionated under high vacuum twotimes to get 50 grams of acid 29 as a light yellow liquid with a purityof 90% as determined by gas chromatography (GC). The pure product 29 wasalso characterized using ¹H NMR spectroscopy in CDCl₃: δ 3.49 (t, 2H,CH₂), 3.89 (t, 2H, CH₂), 4.20 (s, 2H, CH₂), 8.56 (bs, 1H, COOH).

Example 30 Synthesis of (2-Bromo-ethoxy)-acetic acid2-[2-(2-bromo-ethoxy)-acetoxy]-ethyl ester

A solution ethylene glycol (7.5 grams, 120.83 mmoles),(2-Bromo-ethoxy)-acetic acid 29 (48.6 grams, 265.57 mmoles) andpara-toluenesulphonic acid (0.3 grams) in toluene (400 ml) in a 1 lit 4neck round bottom flask equipped with a mechanical stirrer anddean-stark apparatus was refluxed for 8 hours followed by cooling toroom temperature. The toluene layer was washed with water (2×50 ml), 5%sodium bicarbonate solution (2×50 ml), water (2×50 ml) and dried oversodium sulphate and distilled to get crude 30 (33 grams, 69.7%) as lightyellow liquid. GC purity: 86.4%. The pure product 30 was alsocharacterized using ¹H NMR spectroscopy in CDCl₃: δ 3.48 (t, 2H, CH₂),3.88 (t, 2H, CH₂), 4.14 (s, 2H, CH₂), 4.38 (s, 2H, CH₂).

Example 31

To a solution of 4-nitro benzoic acid (40.3 grams, 241.02 mmoles) and 30(2-Bromo-ethoxy)-acetic acid 2-[2-(2-bromo-ethoxy)-acetoxy]-ethyl ester(16.6 grams, 42.33 mmoles) in dimethylformamide (80 ml) was added asolution of triethylamine (21.4 grams, 211.48 mmoles) indimethylformamide (20 ml) drop wise and stirred at 50° C.-60° C. for 24hours. The solids were filtered off, the dimethylformamide solution wasadded onto water (125 ml), extracted with ethyl acetate, washed with 5%sodium bicarbonate solution (2×25 ml), water (2×25 ml), dried oversodium sulphate and distilled to get crude dinitro PDO 31 which waspurified by column chromatography on silica gel using chloroform aseluant to get dinitro PDO as light yellow syrup (7 grams) which over aperiod of 3 days crystallized to a solid which was slurried in hexane toget pure 31 dinitro (5 grams) as off white powder with a melting pointof 75.5-78° C., The pure product 31 was also characterized using ¹H NMRspectroscopy in CDCl₃: δ 3.90 (t, 2H, CH₂), 4.15 (s, 2H, CH₂), 4.37 (s,2H, CH₂), 4.55 (t, 2H, CH₂), 8.26 (dd, 4H, Ar)

Example 32

Dinitro PDO 31 (2 grams, 3.54 mmoles) was dissolved in ethyl acetate (50ml) in a pressure vessel, palladium carbon (10%, 50% wet, 1 gram) addedand the mixture stirred under hydrogen atmosphere (3 Kg) for 2 hours.The catalyst was removed by filtration, ethyl acetate dried over sodiumsulphate and distilled to get crude diamine 32 (1.4 grams, 78.6%) aslight yellow syrup. The crude product 32 was also characterized using ¹HNMR spectroscopy in a mixture of CDCl₃ and DMSO-d₆: δ 3.84 (t, 2H, CH₂),4.15 (s, 2H, CH₂), 4.30 (s, 2H, CH₂), 4.36 (t, 2H, CH₂), 5.15 (bs, 2H,NH₂), 6.56 (d, 2H, Ar), 7.72 (d, 2H, Ar).

Example 33

This monomer is prepared from diamine 32 using the procedures describedin Example 28 of the present patent application.

Example 34 Synthesis of diglycolic acid diacid

Step 1. Synthesis of denzylated diglycolic acid diglycolate:

Into a clean and dry 2 liter, 4 necked round bottom flask equipped witha desiccant tube was added 100 grams of diglycolic acid and 500 ml ofAcetone. The flask was placed in an oil bath maintained at roomtemperature and placed on a magnetic stirrer. To this stifling solutionof diglycolic acid and acetone was added 311.8 ml of triethylaminefollowed by stirring at room temperature for 10 minutes. 302 grams ofbenzyl chloroacetate was added dropwise to the stifling solution usingdropping funnel. The resulting solution was left for stirring at roomtemperature overnight. The progress of the reaction was monitored usingthin layer chromatography. Once the reaction was complete, it wasfiltered and washed with acetone. The filtrate was precipitated in 2liters of cold water and extracted three times each with 300 ml of ethylacetate. The ethyl acetate fraction was dried using sodium sulfate.Ethyl acetate was distilled off and the crude compound was precipitatedwith 300 ml of hexane. The precipitated crude product was filtered toyield 280 grams of white powder. The crude product was finallyrecrystallized using a mixture of hexane and ethyl acetate to yield 260grams of pure benzylated diglycolic acid diglycolate with a meltingpoint of 56-58° C. Benzylated diglycolic acid diglycolate was alsocharacterized using ¹H NMR spectroscopy in CDCl₃, δ 3.32 (s, 2H, CH₂),4.67 (s, 2H, CH₂), 5.18 (s, 2H, CH₂), 7.32 (s, 5H, Ar). Benzylateddiglycolic acid diglycolate undergoes 90% hydrolysis to diglycolic acidin 23 hours at pH 7.0 and 100° C.

Step 2. Debenzylation of benzylated diglycolic acid diacid:

Into a hydrogenation apparatus was added 100 grams of benzylateddiglycolic acid diglycolate dissolved in 250 ml of ethyl acetate. 2grams of 10% palladium on carbon was added to the solution and theresulting reaction mixture in the pressure vessel was purged withhydrogen maintained at a pressure of 3 kg and stirred for 6 hours. Thecompletion of reaction was determined by disappearance of startingmaterial using thin layer chromatography. The reaction mixture aftercompletion was filtered using the high flow bed and washed with ethylacetate. Ethyl acetate was distilled off to yield 55 grams of crudediglycolic acid diacid with a melting point of 90-96° C. The resultingcrude product was purified via crystallization using a mixture of ethylacetate and hexane to yield 40 grams of pure diglycolic acid diacid witha melting point of 96-99° C. Pure diglycolic acid diacid was alsocharacterized using ¹H NMR (CDCl₃) δ 4.35 (s, 2H, CH₂), 4.46 (bs, 1H,COOH), 4.62 (s, 2H, CH₂). Diglycolic acid diacid undergoes 100%hydrolysis to diglycolic acid in 6 hours at pH 7.0 and 100° C.

Example 35 Synthesis of caprolactone functionalized diglycolic acid

Into a clean and dry 1 liter, 4 necked round bottom flask equipped witha desiccant tube was added 30 grams of diglycolic acid and 150 ml ofdimethylformamide (DMF). The flask was placed in an oil bath maintainedat room temperature and placed on a magnetic stirrer. To this stiflingsolution of diglycolic acid and DMF was added 26 ml of triethylaminefollowed by stirring at room temperature for 10 minutes. 31.7 grams of6-bromohexanoate was added dropwise to the stifling solution usingdropping funnel. The resulting solution was left for stirring at roomtemperature overnight. The progress of the reaction was monitored usingthin layer chromatography. Once the reaction was complete, it wasfiltered and washed with acetone. The filtrate was precipitated in 250ml of cold water and extracted three times each with 50 ml of ethylacetate. The ethyl acetate fraction was washed four times each with 50ml of 10% solution of sodium bicarbonate followed by washing with 100 mlof water. The ethyl acetate layer was dried using sodium sulfate. Ethylacetate was distilled off to yield 24 grams of crude product. The crudeproduct was washed with 75 ml of hexane and dried using high vacuum toyield 13.5 grams of light yellow colored caprolactone functionalizeddiglycolic acid. Pure caprolactone functionalized diglycolic acid wasalso characterized using ¹H NMR spectroscopy in CDCl₃, δ 1.4 (m, 2H,CH₂), 1.70 (m, 4H, CH₂×2), 2.32 (t, 2H, CH₂), 3.68 (s, 3H, COOCH₃), 4.18(t, 2H, CH₂), 4.22 (s, 2H, CH₂). Caprolactone functionalized diglycolicacid undergoes 60% hydrolysis to diglycolic acid in 22 hours at pH 7.0and 100° C.

Example 36 Synthesis of caprolactone functionalized diglycolic aciddiacid

Into a clean and dry 1 liter, 4 necked round bottom flask equipped witha desiccant tube was added 25 grams of diglycolic diacid and 250 ml ofdimethylformamide (DMF). The flask was placed in an oil bath maintainedat room temperature and placed on a magnetic stirrer. To this stiflingsolution of diglycolic acid and DMF was added 35 ml of triethylaminefollowed by stirring at room temperature for 10 minutes. 43.5 grams of6-bromohexanoate was added dropwise to the stirring solution usingdropping funnel. The resulting solution was left for stifling at 70° C.for 32 hours. The progress of the reaction was monitored using thinlayer chromatography. Once the reaction was complete, it wasprecipitated in 250 ml of cold water and extracted four times each with250 ml of methyl t-butyl ether (MTBE). The MTBE layer was washed fourtimes each with 5% solution of sodium bicarbonate followed by washingwith 200 ml of water. The MTBE layer was dried using sodium sulfate.MTBE was distilled off to yield 35 grams of crude product. The crudeproduct was purified via column chromatography to yield 24 grams oflight yellow colored caprolactone functionalized diglycolic acid diacid.Pure caprolactone functionalized diglycolic acid diacid was alsocharacterized using ¹H NMR spectroscopy in CDCl₃, δ 1.36 (m, 2H, CH₂),1.63 (m, 4H, CH₂×2), 2.24 (t, 2H, CH₂), 3.6 (s, 3H, COOCH₃), 4.1 (t, 2H,CH₂), 4.2 (s, 2H, CH₂), 4.6 (s, 2H, CH₂).

Example 37 Synthesis of polyester from diglycolic acid diacid

Into a clean and dry 100 ml, 3 necked round bottom flask equipped with anitrogen inlet was added 10 grams of diglycolic diacid, 6.32 grams ofethylene glycol and 2 drops of stannous octanoate solution as acatalyst. The flask was placed in an oil bath maintained at 140° C. andplaced on a magnetic stirrer. The temperature of the reaction mixturewas increased to 180° C. after 2.5 hours. The reaction mixture was leftfor stifling at 190° C. for 6 hours following which the reactiontemperature was reduced to 120° C. and a high vacuum was applied. Thereaction was left for stirring at 120° C. under high vacuum for 28hours. 11 grams of light brown colored syrupy polyester was isolated.Polyester undergoes 100% hydrolysis to diglycolic acid in 8 hours at pH7.0 and 100° C.

Example 38 Synthesis of polyester from diglycolic acid dicaprolactone

Into a clean and dry 100 ml, 3 necked round bottom flask equipped with anitrogen inlet was added 10 grams of diglycolic dicaprolactone, 4.76grams of ethylene glycol and 2 drops of stannous octanoate solution as acatalyst. The flask was placed in an oil bath maintained at 140° C. andplaced on a magnetic stirrer for overnight. The temperature of thereaction mixture was increased to 160° C. after 18 hours. The reactionmixture was left for stirring at 160° C. for another 24 hours followingwhich the reaction temperature was reduced to 100° C. and a high vacuumwas applied for another 18 hours. The reaction was further increased to120° C. under high vacuum for 8 hours followed by further increase to140° C. for another 8 hours. 10 grams of light yellow colored syrupypolyester was isolated.

Example 39 Synthesis of polyester from diglycolic acid diaciddicaprolactone

Into a clean and dry 100 ml, 3 necked round bottom flask equipped with anitrogen inlet was added 10 grams of diglycolic dicaid dicaprolactone,3.6 grams of ethylene glycol and 2 drops of stannous octanoate solutionas a catalyst. The flask was placed in an oil bath maintained at 140° C.and placed on a magnetic stirrer for overnight. The temperature of thereaction mixture was increased to 160° C. after 18 hours. The reactiontemperature was reduced to 100° C. and a high vacuum was applied foranother 18 hours. The reaction was further increased to 140° C. underhigh vacuum for 8 hours followed by further increase to 140° C. foranother 8 hours. 9.5 grams of light brown colored syrupy polyester wasisolated. Polyester undergoes 100% hydrolysis to diglycolic acid in 15hours at pH 7.0 and 100° C.

Hexanedioic acid bis-(5-carboxypentyloxycarbonylmethyl)ester (Adipicacid diglycolate dicaproic acid)

Example-40 Hexanedioic acid dibenzyloxycarbonylmethyl ester (Adipic acidwith benzyl chloro acetate)

To a mixture of adipic acid (50 grams, 342.13 mmol), triethylamine (104grams, 1.026 mol) in acetone (500 ml) in a 1 liter round bottom flaskwas added benzyl chloro acetate (145 grams, 785.4 mmol) drop wise. Thereaction mixture was stirred at room temperature overnight. The reactionmixture was then poured onto cold water to yield crude 40 which wasfiltered, dried and purified by recrystallising from ethyl acetate togive pure 40 (97 grams, 69.7%) as a white powder with 97.9% purity asdetermined by HPLC, m.p: 73-75° C. The pure product 40 was alsocharacterized using ¹H NMR spectroscopy in CDCl₃: δ 1.72 (t, 2H, CH₂),2.42 (t, 2H, CH₂), 4.65 (s, 2H, OCH2), 5.20 (s, 2H, OCH2), 7.38 (m, 5H,Ar).

Example-41 Hexanedioic acid dicarbonylmethyl ester (Adipic acid diacid)

Hexanedioic acid dibenzyloxycarbonylmethyl ester 40 (97 grams, 219.46mmol) was dissolved in ethyl acetate (400 ml) in a pressure vessel, 50%wet Palladium on carbon (5%, 20 grams) added and the mixture was leftfor stirring under an atmosphere of hydrogen (4 Kg) for 4 hours and 15minutes. The catalyst was removed by filtration and the ethyl acetatewas distilled off under vacuum and precipitated to yield crude 41 byaddition of hexane. The crude was filtered off, dried and purified byrecrystallisation in ethyl acetate to get pure 41 (30.8 grams) as awhite powder with a melting point of 108-110° C., Mass: M−1=261.1. Thepure product 41 was also characterized using ¹H NMR spectroscopy inDMSO-d₆: δ 1.72 (t, 2H, CH₂), 2.42 (t, 2H, CH₂), 4.65 (s, 2H, OCH2),5.20 (s, 2H, OCH2), 7.38 (m, 5H, Ar).

Example-42 Hexanedioic acid bis-(5-benzyloxycarbonylpentyloxycarbonylmethyl) ester (benzyl adipic diglycolate dicaproate)

To a mixture of hexanedioic acid dicarbonylmethyl ester 41 (30 grams,205.28 mmol), triethylamine (48 ml, 344.38 mmol) in acetone (300 ml) ina 1 liter round bottom flask was added benzyl 6-bromo hexanoate (72grams, 252.63 mmol) drop wise. The reaction mixture was stirred at roomtemperature overnight and poured onto cold water to yield crude 42.Crude 42 was then extracted into ethyl acetate and dried over sodiumsulphate. The ethyl acetate was distilled off under reduced pressure andpurified by column chromatography on silica gel using chloroform: ethylacetate as eluant to give pure 42 (35 grams) as light yellow syrup.Mass: M+1=671, The pure product 42 was also characterized using ¹H NMRspectroscopy in CDCl₃: δ 1.24 (t, 2H, CH₂), 1.36 (m, 2H, CH₂), 1.70 (m,4H, CH₂), 2.34 (t, 2H, CH₂) 2.40 (t, 2H, CH₂), 4.12 (t, 2H, OCH2), 4.55(s, 2H, OCH2), 5.08 (s, 2H, OCH2), 7.32 (m, 5H, Ar).

Example-43 Synthesis of hexanedioic acidbis-(5-carboxy-pentyloxycarbonyl methyl) ester (adipic acid diglycolatedicaproic acid)

Hexanedioic acid bis-(5-benzyloxycarbonyl-pentyloxycarbonylmethyl) ester42 (33 grams, 49.25 mmol) was dissolved in ethyl acetate (200 ml) in apressure vessel, 50% wet Palladium on carbon (5%, 8 grams) added and themixture stirred under an atmosphere of hydrogen (4 Kg) for 19 hours. Thecatalyst was removed by filtration and distilled off the ethyl acetateunder vacuum and precipitated the crude by adding hexane, filtered anddried to get pure 43 (20 grams) as a white powder with a melting pointof 96-99° C., Mass: M+Na=512. The pure product 43 was also characterizedusing ¹H NMR spectroscopy in CDCl₃: δ 1.24 (t, 2H, CH₂), 1.36 (m, 2H,CH₂), 1.70 (m, 4H, CH₂), 2.34 (t, 2H, CH₂) 2.40 (t, 2H, CH₂), 4.12 (t,2H, OCH2), 4.55 (s, 2H, OCH2), 5.08 (s, 2H, OCH2), 7.32 (m, 5H, Ar).

Adipic tetraglycolic acid

Example-44 Synthesis of hexanedioic aciddibenzyloxycarbonylmethoxycarbonylmethyl ester (benzyl adipictetraglycolate)

To a mixture of hexanedioic acid dicarbonylmethyl ester 41 (30 grams,205.28 mmol), triethylamine (35 grams, 334.8 mmol) in acetone (300 ml)was added benzyl chloro acetate (46.5 grams, 251.87 mmol) dropwise andstirred at room temperature overnight. The reaction mixture was pouredonto cold water and crude 44 was extracted into ethyl acetate, driedover sodium sulphate, distilled under reduced pressure and purified bycolumn chromatography on silica gel using chloroform: ethyl acetate aseluant to give pure 44 (53 grams as a light yellow syrup. Mass:M+=558.9. The pure product 44 was also characterized using ¹H NMRspectroscopy in CDCl₃: δ 1.68 (t, 2H, CH₂), 2.36 (t, 2H, CH₂), 4.64 (s,4H, OCH2), 5.12 (s, 2H, OCH2), 7.26 (m, 5H, Ar)

Example-45 Synthesis of hexanedioic acid dicarbonylmethoxycarbonylmethyl ester (adipic tetra glycolic acid)

Into a solution of hexanedioic aciddibenzyloxycarbonylmethoxycarbonylmethyl ester 44 (116 grams, 262.44mmol) in ethyl acetate (600 ml) in a pressure vessel was added 50% wetpalladium on carbon (5%, 20 grams) and the mixture was left for stiflingunder an atmosphere of hydrogen (4 Kg) for 19 hours. The catalyst wasremoved by filtration and ethyl acetate was distilled off under vacuumfollowed by precipitation in hexane to yield crude 45, which wasfiltered and dried to get pure 45 (29 grams) as a white powder with amelting point of 111-115° C., Mass: M+1=379, The pure product 45 wasalso characterized using ¹H NMR spectroscopy in a mixture of CDCl₃ andDMSO-d₆: δ 1.68 (t, 2H, CH₂), 2.36 (t, 2H, CH₂), 4.52 (s, 2H, OCH₂),4.64 (s, 2H, OCH₂)

Caprolactone diamine tetraglycolic acid

Example-46 Synthesis of benzylated caprolactone diamine tetraglycolate

To a mixture of caprolactone diamine (50 grams, 105.80 mmol), anhydrousK₂CO₃ (220 grams, 1.592 mol), sodium iodide (80 grams, 533.72 mmol) inanhydrous acetone (1000 ml) in a 3 liter round bottom flask was addedbenzyl chloro acetate (157.5 grams, 853.66 mmol) and refluxed for 48hours. Acetone was distilled off and water (500 ml) was added. Crude 46was extracted into ethyl acetate, dried over anhydrous sodium sulphate,distilled of solvent under reduced pressure and the residue purified bycolumn chromatography on silica gel using hexane:ethyl acetate to getpure 46 (84 grams) as a light yellow syrup. Mass: M+=1064.8. The pureproduct 46 was also characterized using ¹H NMR spectroscopy in CDCl₃: δ1.48 (m, 2H, CH₂), 1.70 (m, 4H, CH₂), 2.34 (t, 2H, CH₂), 3.82 (t, 2H,CH₂), 4.06 (s, 4H, CH₂), 4.24 (s, 2H, CH₂), 5.08 (s, 4H, CH₂), 6.52 (d,2H, Ar), 6.70 (d, 2H, Ar), 7.25 (m, 10H, Ar).

Example-47 Synthesis of Caprolactone diamine tetraglycolic acid

Benzylated caprolactone diamide 46 (10 grams) was dissolved in 100 ml ofdry ethyl acetate in a pressure vessel. 50% wet palladium on carbon(10%, 3 grams) was added to the reaction mixture and the mixture wasleft for stifling under an atmosphere of hydrogen (4 Kg) overnight. Thecatalyst was removed by filtration and 80% of the Ethyl acetate wasdistilled off to get the crude 47, which was purified by suitable methodto get pure 47. M.p: Mass: M+, ¹H NMR (DMSO-d₆).

Glycolate Diamide Diol

Example-51 Synthesis of Benzylated glycolate diamide

To a solution of ethylene glycol diglycolate diamine (50 grams, 138.74mmol) in DMF was added triethylamine (68 ml, 487.87 mmol) cooled to 10°C. under N₂ atmosphere; added benzyloxy acetyl chloride (76.8 gm, 416.26mmol) drop wise and further stirred overnight at room temperature. TheTLC showed the presence of unreacted ethylene glycol diglycolatediamine, so further quantity of benzyloxy acetyl chloride (10 gm, 54.20mmol) in DMF (50 ml) was added and stirred at room temperature overnight, reaction mass poured onto cold water, precipitated solid wasfiltered dried and recrystallised from ethyl acetate:hexane (1:6)filtered the pure product to get pure 51 (56 gm) as white powder with amelting point of 111-112° C., Mass: M+=656. The pure product 51 was alsocharacterized using ¹H NMR spectroscopy in a mixture of CDCl₃ andDMSO-d₆: δ 4.02 (s, 2H, CH₂), 4.40 (s, 2H, CH₂), 4.64 (s, 4H, CH₂), 6.82(d, 2H, Ar), 7.36 (m, 5H, Ar), 7.54 (d, 2H, Ar)

Example-52 Synthesis of Glycolate diamide diol

Benzylated Glycolate Diamide 51 (50 grams) was dissolved in DMF (300 ml)in a pressure vessel, 50% wet palladium on carbon (5%, 12 grams) addedand the mixture stirred under an atmosphere of hydrogen (4 Kg)overnight. The catalyst was removed by filtration and distilled off 80%of the DMF and precipitated by adding to cold water, filtered and driedto get pure 52 (20 gm) as a white powder with a melting point of180-183° C., Mass: M+=476. The pure product 52 was also characterizedusing ¹H NMR spectroscopy in a mixture of CDCl₃ and DMSO-d₆: δ 3.96 (s,2H, CH₂), 4.36 (s, 2H, CH₂), 4.72 (s, 4H, CH₂), 6.86 (d, 2H, Ar), 7.58(d, 2H, Ar), 9.54 (s, 1H, NH).

When ranges are used herein for physical properties, such as molecularweight, or chemical properties, such as chemical formulae, allcombinations and subcombinations of ranges and specific embodimentstherein are intended to be included.

The disclosures of each patent, patent application and publication citedor described in this document are hereby incorporated herein byreference, in their entireties.

When any variable occurs more than one time in any constituent or in anyformula, its definition in each occurrence is independent of itsdefinition at every other occurrence. Combinations of substituentsand/or variables are permissible only if such combinations result instable compounds.

It is believed the chemical formulas and names used herein correctly andaccurately reflect the underlying chemical compounds. However, thenature and value of the present invention does not depend upon thetheoretical correctness of these formulae, in whole or in part. Thus itis understood that the formulas used herein, as well as the chemicalnames attributed to the correspondingly indicated compounds, are notintended to limit the invention in any way, including restricting it toany specific tautomeric form or to any specific optical or geometricisomer, except where such stereochemistry is clearly defined.

Those skilled in the art will appreciate that numerous changes andmodifications maybe made to the preferred embodiments of the inventionand that such changes and modifications maybe made without departingfrom the spirit of the invention. It is, therefore, intended that theappended claims cover all such equivalent variations as fall within thetrue spirit and scope of the invention.

What is claimed is:
 1. A hydrolysable linker selected from a compound offormula V, VI, VII, and VIII:

wherein: R′ and R″ are each independently a C₁₋₂₄ alkylene diradical,wherein from 1-4 of the CH₂ groups within the alkyl chain are optionallyindependently replaced by O or S atoms, such that each of said O or Satoms is attached only to carbon atoms in the alkyl chain, with theproviso that multiple heteroatoms must be separated from each other andfrom the diradical chain ends by at least one carbon atom; each a isindependently an integer from 0 to 6; each b is independently an integerfrom 1 to 6; each X is independently: —OC(═O)CH₂— (inverse glycolic acidmoiety), —OC(═O)CH(CH₃)— (inverse lactic acid moiety),—OC(═O)CH₂OCH₂CH₂— (inverse dioxanone acid moiety),—OC(═O)CH₂CH₂CH₂CH₂CH₂— (inverse caprolactone acid moiety),—OC(═O)(CH₂)_(y)—, or —OC(═O)CH₂(OCH₂CH₂)_(z)—; each X¹ isindependently: —CH₂C(═O)O— (glycolic acid moiety), —CH(CH₃)C(═O)O—(lactic acid moiety), —CH₂CH₂OCH₂C(═O)O— (dioxanone acid moiety),—CH₂CH₂CH₂CH₂CH₂C(═O)O— (caprolactone acid moiety), —(CH₂)_(y)C(═O)O—,or —(CH₂CH₂O)_(z)CH₂C(═O)O—; each Y is independently: —OCH₂C(═O)—(inverse glycolic ester moiety), —OCH(CH₃)C(═O)— (inverse lactic estermoiety), —OCH₂CH₂OCH₂C(═O)— (inverse dioxanone ester moiety),—OCH₂CH₂CH₂CH₂CH₂C(═O)— (inverse caprolactone ester moiety),—O(CH₂)_(m)C(═O)—, or —O(CH₂CH₂O)_(n)OCH₂C(═O)—; each Y¹ isindependently: —C(═O)CH₂O— (glycolic ester moiety), —C(═O)CH(CH₃)O—(lactic ester moiety), —C(═O)CH₂OCH₂CH₂O— (dioxanone ester moiety),—C(═O)CH₂CH₂CH₂CH₂CH₂O— (caprolactone ester moiety), —C(═O)(CH₂)_(m)O—,or —C(═O)CH₂O(CH₂CH₂O)_(n)—; and each m, n, y, and z is independently aninteger selected from 2 to
 24. 2. The linker of claim 1, wherein: R′ andR″ are each independently a C₁₋₂₄alkylene diradical, wherein from 1-3 ofthe CH₂ groups, within the alkyl chain are optionally independentlyreplaced by O or S atoms, such that each of said O or S atoms isattached only to carbon atoms in the alkyl chain, with the proviso thatmultiple heteroatoms must be separated from each other and from thediradical chain ends by at least one carbon atom; each a isindependently an integer from 0 to 6; each b is independently an integerfrom 1 to 6; each X is independently: —OC(═O)CH₂—, —OC(═O)CH(CH₃)—,—OC(═O)CH₂OCH₂CH₂—, or —OC(═O)CH₂CH₂CH₂CH₂CH₂—; more preferably—OC(═O)CH₂— or —OC(═O)CH(CH₃)—; each X¹ is independently: —CH₂C(═O)O—,—CH(CH₃)C(═O)O—, —CH₂CH₂OCH₂C(═O)O—, or —CH₂CH₂CH₂CH₂CH₂C(═O)O—, morepreferably —CH₂C(═O)O— or —CH(CH₃)C(═O)O—; each Y is independently:—OCH₂C(═O)—, —OCH(CH₃)C(═O)—, —OCH₂CH₂OCH₂C(═O)—, or—OCH₂CH₂CH₂CH₂CH₂C(═O)—, more preferably —OCH₂C(═O)— or —OCH(CH₃)C(═O)—;each Y¹ is independently: —C(═O)CH₂O—, —C(═O)CH(CH₃)O—,—C(═O)CH₂OCH₂CH₂O—, or —C(═O)CH₂CH₂CH₂CH₂CH₂O—; more preferably—C(═O)CH₂O— or —C(═O)CH(CH₃)O—; and each m, n, y, and z is independentlyan integer from 2 to
 24. 3. The linker of claim 2, wherein: R′ and R″are each independently a C₁₋₂₄alkylene diradical, wherein from 1-3 ofthe CH₂ groups, within the alkyl chain are optionally independentlyreplaced by O or S atoms, such that each of said O or S atoms isattached only to carbon atoms in the alkyl chain, with the proviso thatmultiple heteroatoms must be separated from each other and from thediradical chain ends by at least one carbon atom; each a isindependently an integer from 0 to 6; each b is independently an integerfrom 1 to 6; each X is independently: —OC(═O)CH₂— or —OC(═O)CH(CH₃)—;each X¹ is independently: —CH₂C(═O)O— or —CH(CH₃)C(═O)O—; each Y isindependently: —OCH₂C(═O)— or —OCH(CH₃)C(═O)—; each Y¹ is independently:—C(═O)CH₂O— or —C(═O)CH(CH₃)O—; and each m, n, y, and z is independentlyan integer from 2 to
 24. 4. The linker of claim 1, wherein the linker isof Formula V.
 5. The linker of claim 2, wherein the linker is of FormulaV.
 6. The linker of claim 3, wherein the linker is of Formula V.
 7. Thelinker of claim 1, wherein the linker is of Formula VI.
 8. The linker ofclaim 2, wherein the linker is of Formula VI.
 9. The linker of claim 3,wherein the linker is of Formula VI.
 10. The linker of claim 1, whereinthe linker is of Formula VII.
 11. The linker of claim 2, wherein thelinker is of Formula VII.
 12. The linker of claim 3, wherein the linkeris of Formula VII.
 13. The linker of claim 1, wherein the linker is ofFormula VIII.
 14. The linker of claim 2, wherein the linker is ofFormula VIII.
 15. The linker of claim 3, wherein the linker is ofFormula VIII.
 16. The linker of claim 1, wherein the linker is selectedfrom:

wherein n is an integer selected from 10 to
 50. 17. The linker of claim1, wherein the linker is selected from:

wherein n is an integer from 10 to
 50. 18. The linker of claim 17,wherein n is an integer from 10 to
 30. 19. The linker of claim 17,wherein n is an integer from 10 to
 20. 20. The linker of claim 17,wherein n is an integer from 10 to about
 12. 21. The linker of claim 1,wherein the linker is selected from:

wherein n is an integer from 10 to 12.